ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
Recently Viewed
You have not visited any articles yet, Please visit some articles to see contents here.
CONTENT TYPES

Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design

Cite this: J. Med. Chem. 2021, 64, 14, 9786–9874
Publication Date (Web):July 2, 2021
https://doi.org/10.1021/acs.jmedchem.1c00790
Copyright © 2021 American Chemical Society
Subscribed Access
Article Views
2310
Altmetric
-
Citations
-
LEARN ABOUT THESE METRICS
PDF (8 MB) OpenURL HONG KONG UNIV SCIENCE TECHLGY

Abstract

Acetals and ketals and their nitrogen and sulfur homologues are often considered to be unconventional and potentially problematic scaffolding elements or pharmacophores for the design of orally bioavailable drugs. This opinion is largely a function of the perception that such motifs might be chemically unstable under the acidic conditions of the stomach and upper gastrointestinal tract. However, even simple acetals and ketals, including acyclic molecules, can be sufficiently robust under acidic conditions to be fashioned into orally bioavailable drugs, and these structural elements are embedded in many effective therapeutic agents. The chemical stability of molecules incorporating geminal diheteroatomic motifs can be modulated by physicochemical design principles that include the judicious deployment of proximal electron-withdrawing substituents and conformational restriction. In this Perspective, we exemplify geminal diheteroatomic motifs that have been utilized in the discovery of orally bioavailable drugs or drug candidates against the backdrop of understanding their potential for chemical lability.

Introduction

ARTICLE SECTIONS
Jump To

Structural elements in which two heteroatoms, either oxygen, nitrogen, or sulfur or combinations thereof (Figure 1), are bound to a single sp3 carbon atom are often perceived as being problematic scaffolds for the design of drug candidates intended for oral delivery based on an anticipation of instability in the acidic environment of the stomach and the upper gastrointestinal (GI) tract. While this concern may be considered more acute for acyclic derivatives, there are many examples where molecules incorporating geminal diheteroatomic motifs have been gainfully exploited in the design of orally administered drugs and drug candidates, including compounds with acyclic topologies. These motifs find application in situations that take advantage of their specific properties, which can be readily manipulated by the careful selection and deployment of proximal substituents that can confer robust chemical stability under acidic conditions.(1,2) Nevertheless, there are circumstances where geminal diheteroatomic motifs can be labile at low pH or lability can be specifically incorporated by design, with buffered formulations providing a potential drug delivery solution for sensitive molecules that need to be delivered intact by the oral route.(3) However, molecules incorporating diheteroatomic motifs can still be viewed with suspicion as either “unorthodox” or “atypical” functionality to deploy in drug discovery campaigns.(2) Interestingly, Nature relies upon such linkages for the assembly of two of the three major natural polymers, with oligonucleotide concatenation dependent on an N–C–O linkage while the carbohydrate monomers of polysaccharides are connected via O–C–O moieties (Figure 2).(4,5) These bonds offer excellent stability in water at neutral pH with half-lives estimated at between 70 and 230 years for deoxyribonucleic acid (DNA) at 25 °C, of particular importance for information storage, and 20 to 1.2 × 107 years for carbohydrates.(6) Thus, Nature has developed families of enzymes to cleave the N–C–O and O–C–O linkages in nucleotides and carbohydrates.(7,8) A wide range of natural products also incorporate acetal and ketal moieties and their sulfur and nitrogen homologues, with a representative selection of the structures captured by 119 in Figure 3.(9) With many of these naturally occurring compounds, biosynthetic accessibility often relies upon inherent chemical reactivity manifolds in which electrophilic species are intercepted in an inter- or intramolecular fashion by an oxygen-, nitrogen- or sulfur-based nucleophile.(9) Despite the view that geminally disposed diheteroatomic motifs might be considered as unconventional vehicles for drug discovery, these structural elements are actually quite prevalent in marketed, orally administered drugs, with a representative selection presented in Figure 4 that collates examples of embedded O–C–O, O–C–N, N–C–N, O–C–S, N–C–S, and S–C–S motifs. Indeed, these motifs have been widely deployed as scaffolds and appendages in a range of circumstances that includes those that demand sufficient stability for oral administration. There are well in excess of 90 drugs currently on the market that incorporate geminal diheteroatomic motifs, with a particular prevalence in therapeutics for infectious diseases where nucleoside analogues and the penicillin and cephem antibiotics are large and prominent classes of N–C–O and N–C–S derivatives, respectively. The inherent stability of geminal diheteroatomic motifs toward hydrolysis or degradation can readily be modulated by judicious compound design that takes advantage of electronic attributes, strain, or steric effects, all of which can be deployed individually or in combination to either stabilize or destabilize a specific functionality toward degradation. The stabilization of geminal diheteroatomic motifs by the incorporation of proximal electron-withdrawing moieties has proven to be a particularly useful approach, with fluorination (F, CF3) perhaps the most common contemporary tactic.(10) However, these motifs can also be specifically exploited to take advantage of chemical instability as part of the engineering of a drug delivery system or a prodrug moiety that depends on a degradation pathway or a self-immolative element.(10c,11) The presence of geminal diheteroatomic motifs in biologically active molecules is not always overtly acknowledged, but the unique properties that are frequently conferred by their application can offer an advantage in problem-solving during candidate optimization. In this Perspective, we provide a synopsis of some of the more prominent and practically useful applications of geminal diheteroatomic motifs in the design of orally bioavailable drugs in a fashion that highlights their attributes while capturing their potential liabilities. Applications of geminal diheteroatomic motifs that are designed as immolating elements in drug delivery or prodrug design will not be discussed.

Figure 1

Figure 1. Structural elements with two heteroatoms, either oxygen, nitrogen, or sulfur or combinations thereof bound to a single sp3 carbon atom that have been exploited in drug design.

Figure 2

Figure 2. Naturally occurring polymers with nucleic acid oligomers and polysaccharides dependent upon geminal diheteroatomic linkages (marked in red), while polypeptides rely upon amide bonds for concatenation.

Figure 3

Figure 3. Select naturally occurring compounds 119 that incorporate geminal diheteroatomic motifs, which are marked in red.

Figure 4

Figure 4. Geminal diheteroatomic motifs that are present in marketed oral drugs, which are highlighted in red.

Acetals and Ketals (R–O–C–O–R′)

Despite their natural abundance and the prevalence of successful applications in modern drug discovery, acetals and ketals are still frequently considered to be unconventional structural elements not well-suited for contemporary drug design due to the long-held prejudice that these groups are too labile to survive the acidic environment of the stomach.(1,2) However, as shown by the anticonvulsant topiramate (20), the antiemetic aprepitant (21), and many other marketed drugs, even rather simple ketals and acetals that lack overt stabilizing elements (referred to here as nonstabilized) can be resistant to hydrolytic degradation in the gut.(12,13) Indeed, the dioxolane moiety is embedded in 24 drugs approved by the United States Food and Drug Administration (FDA) prior to 2018, and this ring system was the fifth most prevalent oxygen-containing heterocycle in marketed compounds at that time, a ranking viewed with some surprise.(14) Concerns around chemical stability can be addressed by the judicious introduction of proximal electron-withdrawing groups, basic amines or heteroaryl rings, or the careful implementation of steric and strain effects that can be used to enhance the stability of inherently fragile ketal and acetal derivatives. Compounds incorporating such elements are referred to here as stabilized acetals and ketals. Moreover, the introduction of oxygen atoms into a molecule in the context of an acetal or ketal moiety offers the potential for a favorable H-bonding interaction with a drug target or a productive influence on the conformation of a molecule.(13)
The degradation rate of acetals and ketals is determined by several factors, with the basicity of the oxygen atom and the facility with which it protonates (Scheme 1, step 1) and the stability of the carboxonium (carbonylonium) ion intermediate (Scheme 1, step 2) the most prominent influences.(15) The mechanism of hydrolysis thus varies based on inherent structural attributes, with substrate protonation (SE2 mechanism), carboxonium (carbonylonium) ion formation (A1 mechanism,) or reaction of the protonated form directly with H2O or another nucleophile (A2 mechanism) the rate-limiting step.(15a−d,16) The rate of hydrolysis will depend on the mechanism of the reaction, which can clearly be readily influenced by electronic effects, but steric factors can also play a role, as does substitution pattern and, for cyclic acetals and ketals, ring size.(15e,f,h,16,17) Oxygen basicity will influence the population of the protonated form, while electronic stabilization of the carboxonium (carbonylonium) ion intermediate will promote a faster rate of hydrolysis via the A1 pathway.(15e,f,18) Hence, proximal electron-withdrawing substituents confer higher stability to acetals and ketals by both reducing the extent of protonation and/or destabilizing the carboxonium (carbonylonium) ion intermediate, thereby slowing the rate of dissociation of the alcohol.(17d,19) This is illustrated by the measured equilibrium constants between the series of aldehydes and ketones in H2O, MeOH, or EtOH collated in Table 1, where the data capture the effect of a range of electronic properties on the reactivity of structurally simple carbonyl-containing compounds.(20) For example, while acetaldehyde (Table 1, entry 1) exhibits a keq of 1.06, trifluoro-substitution (Table 1, entry 8) alters the equilibrium in favor of the hydrated form by 4 orders of magnitude; consequently, trifluoroacetaldehyde exists predominantly in the hydrated form in aqueous solution. Two well-known hydrates are chloral hydrate (Table 1, entry 7 and 22), where the carbonyl moiety is activated toward the hydrated form by the adjacent electron-withdrawing chlorine substituents, and ninhydrin (23), where the central carbonyl is activated by the two flanking ketone moieties.(21,22) Chloral hydrate (22) is a sedative/hypnotic agent used before minor medical or dental surgery or as a short-term treatment for insomnia.(21) Ninhydrin (23) is routinely used in forensic investigations for fingerprint analysis that functions by engaging in a chemical process that relies upon the reaction of the central hydrated carbonyl with the amino terminus of amino acids and peptides.(22) Ketals (and aminals) derived from a range of halogen-substituted ketones 24 have been shown to display extraordinary stability toward acid hydrolysis, oxidation, and thermal degradation.(23) For example, 25 and 26 are stable toward hydrolysis in the presence of concentrated H2SO4 at 150 and 170 °C, respectively, and were impervious to treatment with 20% HCl in CH3OH, 6 N HNO3, and 2 N NaOH at 100 °C for extended periods where they could be recovered unchanged.(23) A large series of halogenated 1,3-dioxolane derivatives has been evaluated for anesthetic activity in mice from which only 2-(trifluoromethyl)-1,3-dioxolane (27) demonstrated the targeted profile, although the compound was anticipated to be flammable at concentrations that would be associated with a clinical effect.(24)

Scheme 1

Scheme 1. Mechanism of Hydrolysis of Ketals and Acetals
Table 1. Equilibrium Constants for Addition Reactions of Carbonyl Compounds with H2O and Alcohols(20)
entrycarbonyl compoundhydration Keq(20a)hemiacetal Keq(20a)hydration Keq (NMR data(20b))
1CH3CHO1.060.50*1.43
2CH3CH2CHO0.850.42*0.7
3CH3COCH31.4 × 10–32.2 × 10–42.0 × 10–3
4CH2ClCOCH30.112.7 × 10–20.1
5CHCl2COCH32.98.1 × 10–22.86
6CH2ClCHONDND370
7CCl3CHONDND2.78 × 103
8CF3CHO2.9 × 1041.2 × 103ND
9CF3COCH3350.88ND
10CF3COCF31.2 × 1063.0 × 103ND
11C6H5COCF378270**ND
12CH3COCOCH3NDND2.0
hemiacetal Keq measured in MeOH except * (EtOH) and ** (H2O)hemiacetal Keq measured in H217O
The data presented in Tables 24 captures the relative and absolute rates of hydrolysis for a series of structurally simple acetals and ketals that offer some instruction for the purpose of drug design, although there are additional molecular modifications that can influence stability and which will be discussed later (vide infra).(15a,e,f,17c) Increasing substitution at the carbon located between the two oxygen atoms increases the rate of hydrolysis, as evidenced by the comparison between 28, 29, and 30 in Table 2 where the Me in 30 increases the hydrolysis rate by 37,000-fold; and 33 and 34 where the Me in 34 enhances the lability by almost 26,000-fold.(15e) Similarly, in the series of dioxolanes 3537, hydrolytic degradation rates increase with substitution at the methylene.(15h) While this was attributed to a steric decompression factor that captures the effect of the collapse of a tetrahedral intermediate to a trigonal alkoxy carboxonium (carbonylonium) ion intermediate, electronic stabilization of the carboxonium (carbonylonium) ion is presumably also a contributing factor. A higher substituted alkoxy element also enhances the rate of hydrolysis, attributed to the increased basicity (proton affinity) of the oxygen atom, as illustrated by the 10-fold difference in rate between the EtO in 32 and the MeO in 31 in Table 2 and 39 and 40 in Table 3. Smaller rings are more stable toward hydrolysis than larger rings (compare 41, 42, and 43 in Table 3) while integrating one of the oxygen atoms as part of an aryl ether moiety slows the rate in the context of a smaller ring (compare 44 with 41, and 45 with 42 in Table 3) but not the larger ring, as illustrated by the comparison between 47 and 43.(10c) In these examples, the hydrolysis rates correlate with proton affinity values. In addition, substituents in the embedded diol can slow the hydrolysis rate, as illustrated by the data compiled for 4853 in Table 4.(17c)
Table 2. Relative Rates of Hydrolysis of the Series of Acetal and Ketal Derivatives 2834 Indexed to 1,3-Dioxane (28)(15e) and the Dioxolanes 3537 Indexed to 35(15h)
Table 3. Relative Rates of Hydrolysis of a Series of Acetal and Ketal Derivatives Indexed to Spiro[benzo[d][1,3]dioxole-2,1′-cyclohexane] (44)(15f)
Table 4. Measured Rate Constants for the Hydrolysis of the Series of Ketal Derivatives 4853(17c)
For the series of benzophenone ketals 5458 compiled in Table 5, a good correlation between the log of the rate of hydrolysis and the Hammett σ constant but a poor correlation with Brown’s σ+ constant was interpreted to indicate that the reaction was associated with substrate basicity (A1 or A2 mechanism) rather than carboxonium (carbonylonium) ion stabilization (SE2 mechanism).(15a,25) This provided an explanation of the observation that the hydrolysis of benzaldehyde diethyl acetal was more rapid than that of benzophenone diethyl ketal, which reacts via an SE2 mechanism.
Table 5. Measured Rate Constants for the Hydrolysis of the Series of Benzophenone-Based Ketal Derivatives 5458(15a)

Drugs and Molecules Incorporating Nonstabilized Acetals and Ketals

Topiramate

One of the most prominent orally bioavailable, ketal-containing drugs is the anticonvulsant topiramate (20) which incorporates two acetone-derived ketal moieties, with one of the dioxolane rings integrated into a third ketal element by virtue of its relationship with the pyran ring.(12) Topiramate (20) is a derivative of the naturally occurring monosaccharide d-fructose and was originally prepared as a synthetic precursor to fructose-1,6-diphosphate analogues designed to block glyconeogenesis. Interestingly, 20 was selected for evaluation as an anticonvulsant in a traditional seizure test conducted in mice simply because it contains the primary sulfonamide group that is a hallmark of acetazolamide (59), a clinically effective anticonvulsant that was introduced in 1952. Indeed, topiramate (20) demonstrated anticonvulsant properties following oral administration to mice in this model. However, the advancement of topiramate (20) was not without its challenges, as enunciated recently by its inventor Bruce Maryanoff: “As the inventor of topiramate, which contains two ketal groups, I have to say how much flack I caught in trying to champion clinical development of the compound. Bunch of naysayers out there, with inherent chemical prejudices. We verified its stability to simulated gastric fluid, and the rest is history: a billion-dollar drug!”(26)
Topiramate (20) was discovered in 1979 and approved by the FDA in 1996, with peak annual sales reaching $2.2 billion as a proprietary drug. In generic form, 20 ranked 89th in sales in the U.S. in 2021 with over 8.5 million annual prescriptions.(27) The 4,5-acetone-derived ketal of 20 is critical for its pharmacological activity since removal (60) or expansion to a cyclohexane ring (61) eliminates the anticonvulsant activity.(28) Despite its low LogP value of 0.5 (a LogP value of 2.0 is optimal for crossing the blood–brain barrier) and relatively high topological polar surface area (TPSA) of 116 Å2 (60–70 Å is optimal for CNS drugs) primarily due to the presence of the primary sulfonamide moiety, 20 readily penetrated the central nervous system (CNS).(29,30) In patients with epilepsy, the median cerebrospinal fluid (CSF)/plasma ratio of total 20 was 0.85.(31) The unbound fraction of 20 in plasma was 84%, while the free fraction in CSF was 97%, and the concentration of 20 in CSF was approximately the same as the unbound proportion of the drug in plasma. Therefore, the plasma concentration of 20 can be used for therapeutic drug monitoring. Interestingly, the hexafluorinated analogue 62, which was prepared to assess the effect of increased lipophilicity on CNS penetration rather than to modulate chemical stability, exhibited poorer activity in the mouse maximal electroshock seizure model screen, with only 40% protection observed at a dose of 75 mpk, which compared to 80% for 20 at a dose of 10 mpk.(28) In humans, the oral bioavailability of 20 is 80%, with the majority (70%) of the drug excreted unchanged in the urine, and the drug has a half-life in plasma of 21 h. In preclinical species (mouse, rat, rabbit, and dog), 89–98% of the dose of 14C-labeled 20 is recovered unchanged in the urine and feces.(32) The remainder of the drug is metabolized, which includes the loss of both ketal elements, with some hydrolysis occurring in the gut during absorption; however, the collective PK data quoted above suggest that hydrolytic decomposition of 20 in the gut is minimal.(32)
The precise mechanisms underlying the pharmacological actions of 20 toward relieving seizures and migraine attacks have not been fully elucidated.(33) However, 20 has been shown to be active on voltage-dependent sodium channels, and both γ-aminobutyric acid (GABA) and glutamate receptors, properties that are likely to contribute to its therapeutic effects. Topiramate (20) enhances GABAergic activity and reduces glutamatergic activity, which attenuates neuronal excitability, thus preventing seizures and migraines.(33) In addition, blocking activity on the voltage-dependent sodium channel may further enhance its antiseizure activity.

Doxofylline

Theophylline (63), which is readily available from natural sources such as tea leaves and cocoa beans, is a bronchodilator that has been used for the treatment of asthma and chronic obstructive pulmonary disease (COPD) since 1930.(34) While effective, theophylline (63) exhibits a narrow therapeutic window, with nausea, stomach and abdominal pain, headache and trouble sleeping among the most common side effects, and is associated with numerous drug–drug interactions (DDIs). Doxofylline (64), which differs from 63 by the presence of a cyclic acetal-containing side chain, demonstrates comparable efficacy in the treatment of respiratory diseases while offering a superior safety profile that is associated with fewer DDIs; notably, 64 exhibits a distinct pharmacological profile to 63.(35) Doxofylline (64) is stable under acidic conditions (0.2% formic acid, 37 °C, 1 h), reflecting the 63% oral bioavailability and t1/2 of 7–10 h observed in humans. The major metabolite in humans is the primary alcohol 67, which is much less active than the parent compound; thus, doxofylline (64) is not considered to be a prodrug of 63 (Scheme 2).(36) A recent study showed that the aldehyde 66 was the most abundant metabolite produced in human liver microsomes (HLM). However, in human plasma, the major metabolites were the alcohol 67 and the carboxylic acid 68, with the aldehyde 66 and the 2′-hydroxyethyl ester of theophylline acetic acid 69 identified as minor components. Thus, the metabolic pathway for 64 in humans involves the CYP450-mediated oxidation of one of the methylenes of the dioxolane ring to afford 65, which precipitates ring opening and collapse of the acetal to give the aldehyde 66, which is either reduced to the alcohol 67 or oxidized to the acid 68 by non-P450 dismutase in the cytosol.(36a) The 2′-hydroxyethyl ester 69 was also observed after incubation with rat liver microsomes (RLM) and was the major metabolite in this experiment, which presumably arose from cytochrome P450 (CYP450)-induced oxidation of the dioxolane at the C2 methine to afford 70, which is subject to spontaneous ring opening.(36b)

Scheme 2

Scheme 2. Metabolism of Doxofylline (64)

SSR411298

SSR411298 (71), a potent, reversible inhibitor of fatty acid amide hydrolase (FAAH), is constructed on a 1,3-dioxane heterocyclic ring as the central core element, a structural feature that distinguishes it from other FAAH inhibitors.(37) FAAH is the primary enzyme responsible for degrading the endocannabinoids anandamide (AEA), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA), and oral administration of 71 elicited robust increases in hippocampal levels of AEA, OEA, and PEA in mice. SSR411298 (71) demonstrated significant efficacy in several animal models of anxiety and depression following oral dosing, although details on the PK profile and chemical stability under acidic conditions were not described. SSR411298 (71) was advanced into clinical trials, but a phase II evaluation of the drug for the treatment of pain associated with cancer was terminated in 2010 for strategic reasons, while clinical development for the treatment of depression was discontinued in 2012 after completion of a second phase II study.(38)

GSK 2336805 (HCV NS5A Inhibitor)

GSK2336805 (72) is a structural homologue of daclatasvir (73), a hepatitis C virus (HCV) NS5A replication complex inhibitor that demonstrated potent activity toward a range of clinically relevant genotypes (GTs) and was developed to be used in combination with other drugs to treat HCV infection.(39,40) The differentiating structural element between 72 and 73 is the spiro dioxolane moiety installed on one of the pyrrolidine rings of the former compound.(40) GSK2336805 (72) exhibited inhibitory activity toward wild-type (WT) HCV replicons representing several genotypes that were comparable to 73, but the cyclic ketal analogue appeared to be more potent toward several viruses expressing mutations in the HCV NS5A protein. GSK2336805 (72) was advanced into phase II clinical trials to assess its pharmacokinetic (PK) profile in normal healthy volunteers (NHVs) and its effect on viral load in HCV-infected subjects. In clinical trials, 72 demonstrated inferior oral exposure compared to 73, which was a result of its limited oral absorption rather than presystemic degradation of the ketal moiety.(40b) GSK2336805 (72) accounted for more than 95% of the total drug-related material in human plasma extracts, with two metabolites estimated to account for between <1% and <5% of the dose, respectively, dependent on the dosing regimen. One of the characterized metabolites of 72 was the result of hydroxylation of the unsubstituted pyrrolidine ring adjacent to the ring nitrogen atom at the C5 position, the main path of metabolism for 73, while the other reflected modification of the dioxolane moiety in a fashion attributed to hydrolysis to the ketone which was subsequently reduced to the alcohol; however, this metabolite amounted to <1% of drug-related material following doses of 75 and 120 mg.(40b)

HCV Replication Inhibitors

A series of imidazo[1,2-a]pyridine-based HCV replication inhibitors that appeared to target the NS4B protein and originated with the oxazolidinone-substituted piperidine 74 was developed to incorporate the substituted piperazine amide motif found in 75.(41) The single-crystal X-ray structures of both 74 and 75 revealed a perpendicular orientation of the two cyclic ring systems that, in each case, was calculated to be the lowest energy conformation. Against this backdrop, a spiro ketal moiety was designed as a means of constraining the two ring systems in a mutually orthogonal arrangement anticipated to mimic the preferred conformation. Spiro ketal 76 showed comparable inhibitory activity to the original lead compounds, but its oral bioavailability was moderate due to CYP450-mediated hydroxylation of the piperidine ring on the carbon atom α- to the ketal moiety. This metabolic modification afforded the hydroxylated metabolite 77, which exhibited both enhanced antiviral potency and excellent oral bioavailability.(41) The discovery of these novel spirocyclic compounds as potent HCV NS4B inhibitors demonstrates that spiroketalization can be an effective tool for influencing conformation while offering facile synthetic accessibility and, in this context, excellent oral bioavailability in rats.

Proline Acetal-Based Macrocyclic HCV Inhibitors

The pentapeptide-based ketoamide 78 was identified as a lead mechanism-based HCV NS3/4A protease inhibitor with moderate potency, Ki* = 220 nM.(42a) An X-ray cocrystal structure revealed close proximity of the tert-butyl group bound to the S2 proline and the Boc capping moiety that extends into the P4 subpocket, suggesting the potential for macrocyclization between these two elements that would preorganize the molecule into the preferred conformation.(42b) To test this hypothesis, a substituted bicyclic proline acetal moiety was introduced at S2 while a 2-(3-hydroxyphenyl)acetamide cap at S3 provided a convenient synthetic handle with which to link to the S2 element via a Mitsunobu reaction. These efforts led to the identification of the three macrocycles 7981, where the S2′ moiety was the site of structural variation, with all demonstrating potent enzyme inhibitory activity.(42b) An analysis of the X-ray cocrystal structure of 80 bound to HCV NS3/4A protease indicated that hydrophobic interactions between the S2 bicyclic proline acetal and the protein surface contributed to the excellent potency of the inhibitor. However, the PK properties of these acetal-based macrocycles were not described.

Cyclophilin HCV Inhibitors

The nonimmunosuppressive cyclophilin (Cyp) inhibitor 82, derived from the naturally occurring sanglifehrins that incorporate an unusual piperazic acid moiety, was the basis of an optimization campaign designed to identify a potent HCV inhibitor with oral bioavailability and appropriate PK properties.(43,44) To improve the antiviral and PK profiles of 82, three structural modifications were performed: the styrene element was replaced with a quinoline heterocycle, in which the olefin is incorporated into the phenyl ring of the fused bicyclic moiety; the macrocycle was reduced in size to a 21-membered ring; the C1–O24 lactone and N12–C13 lactam elements were transposed.(44) The latter molecular edit introduced an amide H-bond donor at a site where it could engage the proximal quinoline nitrogen atom in an intramolecular interaction, thus leading to significantly improved membrane permeability and high oral absorption. The C14 geminal dimethyl substituents provided steric bulk to reduce the propensity of esterases to hydrolytically open the lactone ring. The resulting analogue 83 showed excellent oral bioavailability in rats and dogs but suffered from moderate to high metabolic clearance and was a significant activator of the pregnane X receptor (PXR).(45) Cyclization of the geminal dimethyl in 83 to form the spirocyclic 1,3-dioxane found in 84 reduced the measured LogD value from 3.2 to 2.2, a structural edit that conferred lower PXR activation (45% compared to 88% at 15 μM) and improved metabolic stability (predicted human clearance was 0.42 L/h/kg compared to 0.68 L/h/kg). 2-Substituted 1,3-dioxane analogues were not described, presumably because they might be anticipated to be less desirable since 2-methyl- or 2,2-dimethyl-1,3-dioxanes would increase the LogD while significantly reducing the stability of this moiety under acidic conditions (the relative rates of acid-catalyzed hydrolysis of 1,3-dioxolane (35), 2-methyl-1,3-dioxolane (36) and 2,2-dimethyl-1,3-dioxolane (37) are 1:5,100:54,000 (Table 2)).(15h)

Glycine Transporter Inhibitors

In the development of a series of 3,4-disubstituted pyrrolidine sulfonamides as glycine transporter 1 (GlyT1) inhibitors, the 4-fluorophenyl substituent at C3 of the pyrrolidine ring of 85 was replaced with a dioxane ring in 86 as an approach to reducing the overall lipophilicity of the molecule.(46) In this series, lipophilicity correlated well with intrinsic clearance values obtained from liver microsomal studies. The cLogP of dioxane 86 was reduced by almost 3 units compared to the fluorophenyl prototype 85, resulting in a significant reduction in clearance in both HLM and RLM, which translated into a modest increase in oral bioavailability in rats from 25% to 35%. In order to allay concerns about the stability of the dioxane moiety under low pH conditions, 86 was incubated at pH = 1 for 2 days at room temperature with no appreciable amount of hydrolysis observed. The drug developability trends observed with 86 are consistent, in part, with the increase in the fraction of sp3 carbon atoms (Fsp(3)), which has been advocated as a metric for drug-likeness.(47)

Benzodioxole Derivatives

The benzodioxole moiety is a common structural element present in many natural products, as exemplified by piperine (87), the rich flavor in black pepper and long pepper.(48) However, despite being an acetal, the benzodioxole moiety does not appear to have caused overt concern with respect to the hydrolytic potential within the medicinal chemistry community.(15e,f) A benzodioxole element is also embedded in several marketed drugs including the antidepressant paroxetine (88), the phosphodiesterase 5 (PDE5) inhibitor tadalafil (89) used for the treatment of erectile dysfunction, and the anticancer agent etoposide phosphate (90).(49−51) While chemical stability does not appear to be an issue, there are two potential liabilities associated with the benzodioxole moiety in drug discovery and development. First, CYP450 enzymes can metabolize the methylenedioxy moiety to a highly reactive carbene intermediate which binds very tightly to the heme iron atom forming a stable, metabolic intermediate (MI) complex that only slowly dissociates (Scheme 3).(49,52) This can be a source of drug–drug interactions with other medications that are metabolized by CYP450 enzymes. Second, when the MI complex dissociates, a catechol is released, which can undergo CYP450-mediated oxidation to afford an ortho quinone, a reactive alkylating agent that can be a source of toxicity (Scheme 3).(49) One approach to stabilizing the methylenedioxy moiety involves fluorination of the acetal CH2 and the 2,2-difluorobenzodioxole moiety is a feature of the cystic fibrosis transmembrane regulator (CFTR) correctors lumacaftor (91) and tezacaftor (92), drugs that are used to treat cystic fibrosis.(53) This moiety is also deployed in JNJ-42165279 (93), a potent and selective inhibitor of FAAH that is being explored as a treatment for depression, and the camptothecin analogue 94, which was explored as a potential antitumor agent in the context of its prodrug 95.(54,55)

Scheme 3

Scheme 3. Metabolism of the Benzodioxole Moiety Leading to CYP Enzyme Inhibition and the Production of Catechol and ortho-Quinone
The substituted benzodioxole 96 was identified as a novel cannabinoid-1 receptor inverse agonist explored for its potential to treat obesity.(56) Based on molecular modeling of the lead compound 96 and the previously known cannabinoid-1 receptor (CB1R) ligand 97, the para-fluorophenyl residue in 96, which was not critical for binding, was truncated to arrive at the sulfonamide 98, a molecular edit associated with a 6-fold reduction in binding affinity. However, the sulfonamide series, in general, suffered from poor metabolic stability, but the transformation of 98 (hCB1R Ki = 38 nM) to the amide 99 (hCB1R Ki = 28 nM) maintained binding affinity. In an effort to reduce lipophilicity, the central phenyl ring was replaced with a pyridine heterocycle to give 100, which showed both improved binding affinity and aqueous solubility. Despite its attractive potency, the pyridyl series could not be progressed due to instability in weakly acidic media. The instability may result from the presence of the electron-deficient pyridine heterocycle, which, upon protonation, promotes dioxolane ring cleavage to afford a carboxonium (carbonylonium) ion 103 that is stabilized by the two phenyl rings and the enamine moiety (Scheme 4). Intermediate 103 can readily hydrolyze to afford a stable hydroxypyridone 104, providing an example where the properties of acetals and ketals need to be considered holistically in the broader context of molecular structure. Indeed, exchanging the pyridine heterocycle of 100 for a C6-substituted fluorophenyl ring (101) improved hydrolytic stability along with both binding affinity and functional activity as an inverse agonist. The introduction of a fluorine and a 2,4-dichloro substitution pattern to the phenyl rings to give 102 further enhanced chemical stability while also improving metabolic stability by ameliorating oxidative modification of the unsubstituted phenyl ring. Moreover, the two chlorine substituents increased lipophilic interactions with the CB1R binding pocket, thus leading to enhanced potency. The benzo[d][1,3]dioxole derivative 102 elicited a robust, dose-dependent reduction in body weight gain in a 16-day diet-induced obesity rat model following oral administration.(56)

Scheme 4

Scheme 4. Potential Pathway for the Acid-Catalyzed Degradation of [1,3]Dioxolo[4,5-c]pyridine 100

Benzylidene Ketals

Selective muscarinic M2 receptor antagonists have been explored for their potential to treat Alzheimer’s disease, with an interesting series represented by 105 and 107 constructed on a benzylidene ketal scaffold.(57) Of particular note for this chemotype, the ketal 105 was found to be 50-fold more potent than the tetrahydrofuran homologue 106. To assess the issue of chemical stability, 105 was treated with 0.1 N HCl solution for several days, with both the ketal and the benzodioxole moieties remaining intact. In this molecule, the electron-withdrawing sulfone substituent contributes to the observed stability of the ketal functionality of 105 by destabilizing the carboxonium (carbonylonium) ion intermediate 108, further illustrating the need to view a molecule and its functional group connectivity holistically. However, the presence of the basic piperidine may also play a contributory role by forming a salt that will reduce the propensity for protonation of the ketal oxygen atoms. Compound 105 showed good exposure in rodents following oral dosing but poor plasma concentrations in monkeys due to CYP450-mediated cleavage of the benzodioxole moiety, which was addressed by replacing with a p-methoxyphenyl substituent to afford 107.(57)

Miscellaneous Acetals and Ketals

2,2,-Diphenyl-substituted dioxanes and dioxolanes have found application as 5-hydroxytryptamine 1A (5-HT1A) receptor agonists, as represented by 109 and 110, with the latter demonstrating a robust analgesic effect in the formalin and hot plate mouse models of pain following IP administration.(58) Because of its lack of interaction with μ opioid receptors, 110 may be useful in the treatment of acute and chronic pain without the side effects that are typically observed with opioid medications. The achiral 109 was orally bioavailable in rats and readily penetrated the CNS, with a peak concentration of 157.9 nmol/g following a 10 mpk oral dose and a brain to plasma ratio of 420.(58a) In rat models of disease, 109 demonstrated anxiolytic and antidepressant effects following oral doses ranging from 5 to 20 mpk and exhibited an antinociceptive activity in mice following IP dosing at 10 mpk, an effect reversed by a selective 5-HT1A receptor antagonist.(58a)
Guanethidine (111) and guanadrel (112) are orally active, postganglionic adrenergic blocking agents that act by displacing norepinephrine from storage granules in nerve endings and are used as step II or step III drugs for the treatment of hypertension.(59a) Despite some structural similarities, these two molecules exhibit different pharmacokinetic properties. For example, the oral bioavailability of 111 is poor and highly variable, with only 3- 50% reaching the systemic circulation, while 112 demonstrated rapid and nearly complete oral absorption.(59b,c) The difference in t1/2 between the two drugs in humans is also significant, at 12 h for 112 compared to 1.5 days for 111. Both drugs are comparable in efficacy for the treatment of mild to moderately severe hypertension; however, 112 elicited less orthostatic dizziness and diarrhea than 111.(59c) Guanadrel (112) is partially metabolized by the liver to give 2-(2,3-dihydroxypropyl)guanidine (113), but nearly 50% of an orally administered dose appears as unchanged drug in the urine.
Cyclic acetals have also attracted the attention of the agricultural chemical industry with benzpyrimoxan (114), an insecticide that is active toward brown rice planthopper nymphs that extends to strains resistant to existing insecticides, a recent and prominent example.(60) The discovery of 114 began with the pyrimidine 115, which demonstrated an IC90 of 2–10 mg/L in protecting rice seedlings against a brown rice planthopper challenge.(60a) Systematic SAR studies around the phenyl ring and its relationship with the pyrimidine and the 4-position of the heterocycle provided 114, which exhibited an IC90 of 0.3–1 mg/L in the primary assay. However, 114 distinguished itself by virtue of its superior ability to protect plants from brown rice planthopper nymphs for extended periods of time following seedling exposure, referred to as residual efficacy, compared to the standard insecticide agent buprofezin (116) used as a control.(60a) The mode of action of 114 was not definitively determined, but symptoms suggested an effect on the insect growth regulator in a fashion that is distinct from that of 116, which is an inhibitor of chitin synthase.
JNJ-10397049 (117) is a potent and selective orexin (OX) 2 antagonist that was identified after optimization of the screening hit 118.(61a) However, 117 demonstrated poor oral bioavailability in preclinical species, which was attributed to the acid lability of the 2,2,-dimethyl-1,3-dioxane heterocycle in the gut, a property viewed as a significant impediment to optimization of the series.(61b) While attention was redirected to an alternative series also derived from a screening lead, the published SAR survey did not describe specific details surrounding the chemical lability of 117 or evaluate variations of the dimethylated ketal that might have enhanced chemical stability at low pH.
There are several cyclic acetal and ketal derivatives with unique structural attributes that may offer potential in drug design but which have not found extensive application. A particularly interesting example is provided by the 3-aza-6,8-dioxabicyclo[3.2.1]octane-based scaffolds 121 and 122, referred to as BTAa (bicycles from tartaric acid and amino acids), which are readily available by the condensation of an amino acid-derived aldehyde 119 with a tartaric acid 120 (Scheme 5).(62) These molecules have been shown to offer useful opportunities for structural diversification and functional mimicry. The absolute configuration at each chiral center can be translated from the absolute configuration of the chiral centers in the starting materials, which yields a family of 8 amido esters 121 that can be selectively reduced to the cyclic amino esters 122, thereby providing access to a second family of 8 architecturally interesting compounds. These molecules have interesting shapes and properties, with the amine nitrogen atom of 122 weakly basic by virtue of its relationship with the electron-withdrawing oxygen atoms, while the ester of 121 is sufficiently activated to readily react directly with amines under mild conditions to afford amides. A primary focus of study with these heterocycles has been an exploration of their potential to act as peptidomimetics. Both 123 and 124 have been viewed as bicyclic mimics of proline 125 that are readily available synthetically from d-Ser and l-Ser, the latter furnishing a d-Pro mimetic. These motifs could also be considered as bicyclic homologues of pipecolic acid. The 3-aza-6,8-dioxabicyclo[3.2.1]octane 126 has been proposed as a potential mimic of a Gly-Asn dipeptide 127 based on the depicted structural comparison, while other studies have focused on their use as scaffolds for turn mimetics.(62c)

Scheme 5

Scheme 5. Condensation of an Amino Acid-Derived Aldehyde 119 with a Tartaric Acid 120 to Afford 3-Aza-6,8-dioxabicyclo[3.2.1]octanes 121 and Their Reduction to Amines 122
The similarity of the shape of the BTAa ring system with tropane and its analogues has also been recognized, explored in the context of dopamine transporter (DAT) inhibitors.(62e) BTAa analogue 128 retained much of the DAT inhibitory potency of the prototypes 129 and 130 but was a much weaker inhibitor of the serotonin transporter (SERT), thereby offering significantly enhanced selectivity.(62e)
Another structurally interesting bicyclic acetal is dihydrolevoglucosenone (131, Cyrene), which is readily available from cellulose in just two chemical steps and is sufficiently robust to act as a dipolar aprotic solvent that has been advocated as a green solvent.(63a) The stability of 131 has been attributed to a double anomeric effect, but the apposition of the ketone moiety will reduce the proton affinity of the acetal oxygen atoms and destabilize the carboxonium (carbonylonium) ion intermediate that would result from dissociation and thus may be a dominant factor. The ketone moiety of 131 is chemically reactive under some circumstances, which would be anticipated to present some limitations to its application as a solvent.(63b) The measured physical properties of 131 reveal a Kamlet–Taft π* value, a measure of polarity/polarizability, of 0.93, which is comparable to N-methyl pyrrolidone (NMP) (0.90), DMF (0.88), and dimethyl acetamide (DMAc) (0.85) but lower than dimethyl sulfoxide (DMSO) (1.00) and sulfolane (0.96), while the H-bonding potential, assessed by the β value of 0.61, is lower than NMP (0.75), DMF (0.71), DMAc (0.73), and DMSO (0.74) but considerably higher than sulfolane (0.30).(63a) These properties calibrate the physicochemical attributes of 131 and its synthetic precursor levoglucosenone (132) that could be of value in understanding how to gainfully decorate and deploy this ring system for applications in drug design.(63)

Biologically Active Acetals and Ketals Derived from Natural Products

Rifamycins

The rifamycins are a family of macrocyclic antibiotics characterized by the presence of a naphthol ring that is convened between an aliphatic bridge with an integrated lactam-ketal moiety as a bridgehead element.(64) Rifamycin B (133) gained prominence as the first member of the family for which the structure was fully characterized (Scheme 6).(65) However, while 133 exhibited little intrinsic antibiotic activity, its spontaneous transformation to an active compound in aqueous solution stimulated further study, which revealed that the molecule underwent stereoselective oxidation to give rifamycin O (134), which, in turn, was hydrolyzed to the highly active antibiotic rifamycin S (135) (Scheme 6).(66) Mild reduction of the quinone moiety in 135 gave the hydroquinone, known as rifamycin SV (136), which showed good inhibitory activity toward Gram-positive bacteria, including Mycobacterium tuberculosis, and moderate inhibitory activity toward certain Gram-negative bacteria.(64,67) Nevertheless, therapeutic application of 136 is limited by inadequate pharmacokinetic properties, particularly very poor oral bioavailability, as well as a narrow spectrum of antibacterial activity. Thus, numerous analogues of 136 have been prepared with the objective of improving both oral absorption and the plasma t1/2 as well as the activity against mycobacteria and Gram-negative bacteria. During these campaigns, the 3-dialkylaminomethyl derivatives represented by 137 as a prototype were exposed to oxidation with Pb(OAc)2 to give 3-formylrifamycin SV (138) (Scheme 6).(68) This compound was an unexpected degradation product that served as a key precursor to a variety of imines, hydrazones, oximes, and hydrazide-hydrazones, a transformation that ultimately led to the discovery of the orally bioavailable rifampicin (139), which has become a cornerstone of tuberculosis treatment and one of the Essential Medicines defined by the World Health Organization (WHO). In patients infected with active pulmonary tuberculosis, a single 600 mg oral dose of 139 exhibited 93% oral bioavailability, and its elimination half-life increased with dose: the elimination t1/2 was 2.6 h following a 300 mg dose, 3.3 h after a 600 mg dose and 5.1 h following a 900 mg dose.(69) Two major active metabolites of 139 that were identified in humans were 138, found in urine, and 25-desacetylrifampicin (structure not shown), which was isolated from both bile and urine.(69) Notably, in both metabolites, the ketal bridgehead remained intact.

Scheme 6

Scheme 6. Structure of 133 and Its Chemical Degradation and Metabolic Pathways
The mode of action of 139 has been determined to be inhibition of bacterial DNA-dependent RNA polymerase (RNAP).(70) A crystal structure of the core RNAP from Thermus aquaticus complexed with 139 revealed no specific H-bonding interactions between either of the two ketal oxygen atoms and the protein; however, the ketal bridgehead along with the aliphatic bridge provided a favorable bioactive macrocyclic conformation to promote van der Waals interactions with hydrophobic side chains proximal to the naphthol ring and potential H-bond interactions with the three polar groups located on the naphthol ring and the two on the bridge element.
Rifabutin (140) is another rifamycin family member commonly used in patients who experience tolerability issues with rifampins, most prominently those infected with HIV-1/AIDS who are taking antiretroviral agents (Scheme 6).(71) Rifabutin (140) demonstrated higher in vitro potency than 139 against rifampicin-susceptible isolates of M. tuberculosis and retained activity toward certain rifampicin-resistant isolates.(71) The pharmacokinetic properties of 140 in humans following a single dose reflect moderate oral bioavailability of ∼20%, likely due to high biliary excretion and significant presystemic metabolism; however, the elimination t1/2 was long at ∼45 h, supporting a once-daily dosing regimen.(72) The two major metabolites of 140 in humans are 31-hydroxy rifabutin (141) and 25-desacetyl rifabutin (142) in which the ketal and the aminal moieties are retained in both, reflecting their resilience in vivo (Scheme 6).

Etoposide and Teniposide

Podophyllotoxin (143), a mitotic spindle poison isolated from the roots and rhizomes of the mayapple (Podophyllum peltatum), has been used for centuries by Native Americans for both its medicinal and poisonous properties.(51) Podophyllotoxin cream is commonly prescribed as a potent topical antiviral agent to treat genital warts (human papilloma virus, HPV) and the poxvirus molluscum contagiosum, but it is highly toxic if taken internally. To overcome the toxicity issue, extensive semisynthetic studies were performed around 143 that culminated in the development of etoposide (144), a 4,6-acetal glucoside derivative of 143 that incorporates both acyclic and cyclic acetal moieties (Scheme 7).(73) Etoposide (144) forms a ternary complex with the enzyme topoisomerase II and DNA, thereby stalling DNA synthesis.(51) In clinical trials, 144 was shown to be effective in the treatment of a wide range of cancers, especially when used as part of combination chemotherapy. However, the clinical application of 144 has been limited by poor inherent aqueous solubility (116–167 μg/mL at pH values of 1.3–8), which contributed to unpredictable absorption with early formulations, believed to be a function of poor drug dissolution rather than issues associated with membrane permeability and absorption.(51,74) The glycoside moiety in 144 appears to be labile at a pH value of 1.3 while the lactone moiety is the source of instability at higher pH (10) values; chemical stability is maximal between the pH values of 5 and 6.15. The degradation half-life of 144 at pH 1.3 is 2.88 h, but at pH 7.30, the compound is very stable, with a half-life of 27.72 days. Thus, the oral bioavailability of 144 is compromised by poor dissolution and instability in the gut, where the pH value is low. In 1994, a team at Bristol Myers Squibb developed the water-soluble prodrug 90, which, although designed for IV administration, increased the oral bioavailability of etoposide to 81%.(75) The phosphate moiety of 90 presumably facilitates rapid dissolution of the prodrug in the gut, which is cleaved presystemically by alkaline phosphatase, an enzyme expressed abundantly on the brush border membrane, with the absorption of the released 144 sufficiently rapid to avoid precipitation or hydrolytic decomposition.(76) Etoposide phosphate (90) has been widely used for the treatment of small-cell lung cancer, testicular cancer, and lymphomas and is included on the WHO’s List of Essential Medicines.

Scheme 7

Scheme 7. Structure of 143, Its Evolution to 144 and 90, and Metabolism of 144
Teniposide (145), which differs from 144 by the presence of a 2-substituted thiophene heterocycle rather than a methyl substituent bound to the glucopyranoside ring, is not significantly more potent than 144 in terms of intrinsic activity, but its enhanced cellular uptake leads to greater drug accumulation within cells, thus resulting in improved cytotoxicity.(51,77) The oral bioavailability of 145 in humans averages 42%, but there is considerable variability between individuals (20–71%).(51,78) However, despite the potential for oral delivery, 145 is only administered through an intravenous infusion. In humans, 144 and 145 can be metabolized by several pathways, including CYP3A4-mediated demethylation of one of the methoxyl substituents on the E ring to give the catechol metabolite 146, which can be further oxidized to a quinone intermediate 147 by cellular oxidases (Scheme 7).(51,78b,79,80) Both metabolites showed comparable potency toward inhibiting topoisomerase II; however, the quinone metabolite 147 has been suggested to contribute to the occurrence of epipodophyllotoxin-associated secondary myeloid leukemia, a serious complication of acute lymphoblastic leukemia (ALL) therapy.(51,79,81)

Cortiscosteroid 16,17-Ketals

The installation of a 16,17-ketal to the core of the anti-inflammatory corticosteroid triamcinolone (148) led to the family of compounds 149157 that demonstrated increased potency as the result of enhanced binding to a hydrophobic site of the glucocorticoid receptor, with fluoro substituents at C6 and C9 further improving binding affinity and/or selectivity.(14,82) These ketal-based drugs have been used extensively as topical agents to treat a range of skin conditions and as inhaled medications to treat asthma and COPD.(83) The delivery of these ketals by inhalation was developed as an approach to reducing systemic side effects. Regardless of the delivery device used, only a maximum of 10% of the inhaled dose reaches the airways, with the rest of the dose swallowed and absorbed through the GI tract. The drug that reaches the systemic circulation undergoes extensive metabolic inactivation in the liver, as exemplified by budesonide (150), one of the most widely used lung medications in the world.(27) The acetal moiety is hydroxylated at the acetal carbon by microsomal CYP450 enzymes in the liver to afford 158, which sets the stage for spontaneous decomposition to give the hydroxy ester 159 (Scheme 8).(84) Esterase-mediated hydrolysis furnished 16-hydroxyl prednisone (160), an essentially inactive product. When taken orally for the treatment of certain bowel conditions, 150 acts primarily at the local level within the GI tract.(85) In this context, the acetal moiety of 150 not only associates intimately with the glucocorticoid receptor but also functions as a handle for metabolic inactivation in the liver to reduce systemic activity, thereby rendering 150 a soft drug.

Scheme 8

Scheme 8. Metabolism of 150 to Afford 160

9,10-Acetal-Containing Taxoids

Paclitaxel (161) and docetaxel (162) are two of the most important drugs in cancer chemotherapy.(86) However, both compounds are poorly soluble in water, which limits their formulation to detergent-based vehicles such as Cremophor EL (Kolliphor EL) or Tween 80, both of which are frequently associated with untoward hypersensitivity reactions and require preventative premedication with antihistamines or corticosteroids.(87) In addition, both drugs are administered intravenously and are unsuitable for oral use due to poor oral bioavailability. In order to improve the aqueous solubility, a basic amine was introduced onto the 9,10-acetal ring of the paclitaxel homologue 163 using a methylene spacer to afford the morpholine derivative 164 and the dimethylamine analogue tesetaxel (165), where the absence of the C-7 hydroxyl substituent enhances potency.(88a−e) The acetal moiety enhanced antitumor activity, and the side-chain amine contributed to improved solubility and oral bioavailability while also providing a site for protonation that may help to protect the acetal from acid-mediated degradation.(88a−e) Both 164 and 165 significantly suppressed tumor growth over a wide dosage range following both IV and PO administration in a mouse B16 melanoma model. Moreover, administration of the drugs at the same dosage by both routes produced comparable tumor growth inhibition and body weight loss, indicative of excellent oral bioavailability in mice for both compounds.(88d) Thus, in this context, the amine-substituted acetal moiety in 164 and 165 appears to possess chemical and metabolic stability suitable for oral delivery. Tesetaxel (165) was advanced into clinical trials as an orally bioavailable taxane where it was well absorbed and was associated with a long terminal t1/2 of 167 ± 77 h.(88f,h,h) Although 165 demonstrated responses when explored as a second line monotherapeutic agent in patients with nonsmall cell lung cancer, development was recently abandoned after completing several phase 2 clinical trials in HER2 negative breast cancer patients and a phase 3 clinical trial in triple-negative breast cancer patients.(88i,j)

3,6-Ketal Macrolides

Bovine respiratory disease (BRD) is caused by a bacterial infection that adversely affects beef cattle across the globe but can be treated effectively with antibiotic therapy. Although azithromycin (166) exhibits broad-spectrum antibacterial activity and a long tissue half-life and could be an effective therapy, it has not been given consideration for the treatment of BRD because of the potential for the development of drug-resistant bacteria, which may render it less effective in the treatment of community-acquired bacterial infections in humans. In an effort to discover structurally novel macrolide antibiotics, the acid-labile cladinose sugar was removed, and the exposed C3 hydroxyl was hybridized with the proximal C6 hydroxyl to produce a series of 3,6-ketal derivatives.(89) These ketals, which presumably provide conformational constraint in a fashion that complements the binding site, exhibited potent antibacterial activity toward several key veterinary pathogens, including Staphylococcus aureus and Pasteurella multocida. In a mouse model of intramammary infection, 167 and 168 demonstrated clearance of Staphylococcus aureus in most of the murine mammary glands following subcutaneous injection at a dose of 15 mpk.(89) These ketals may be useful in the treatment of dairy cattle mastitis caused by bacterial infections. However, the oral bioavailability profiles of these ketals remain unknown, and in this case, the 3,6-ketals appear to have been explored primarily for the purpose of structural novelty.

Glycosides

While glycosides are susceptible to degradation by glycoside hydrolases and may be labile under acidic conditions, they can, nevertheless, possess adequate oral bioavailability for therapeutic application as represented, for example, by etoposide phosphate (90) (vide supra) and the second-generation macrolide antibiotics azithromycin (166) and clarithromycin (169). Degradation of 166 to the descladinose derivative was observed after both oral and IV administration, with much higher amounts of this product observed after oral dosing due to exposure to stomach acid.(90,91) However, the impact of cladinose cleavage on the oral bioavailability of 166 appears to be rather limited since the major factor responsible for the moderate oral bioavailability (12%) is incomplete oral absorption; rather, the slow and poor absorption may prolong exposure of the drug to the deleterious effects of stomach acid.(91) The presence of the macrocyclic tertiary amine in 166, which contains two acyclic acetal moieties, results in a much longer serum half-life (35–96 h in humans) and exceptional uptake in tissues, particularly in the lungs, where the half-life is 132 h, and tonsil and prostate tissues. As such, a three-day dose pack of 166 is used to treat many different types of infection while 169 generally requires BID dosing for 7–14 days for efficacy.(91)
Cardiac glycosides have been used for centuries to treat patients with heart disease, and the most commonly prescribed drug of this class is digoxin (170), which is obtained from the purple foxglove flower.(92) Despite the potential for lactone hydrolysis, the presence of a trisaccharide moiety that incorporates three acyclic ketal moieties and seven hydroxyl substituents that might be expected to adversely affect membrane permeability, and the high molecular weight (MW = 830), 170 exhibits high oral bioavailability in humans (F = 71%) and is associated with a plasma t1/2 of 36 h.(93a) The major metabolite of 170 in the blood and urine collected from patients is dihydrodigoxin (171) which results from the enzymatic reduction of the olefin located in the lactone moiety, with both the glycosides and the lactone appearing to be relatively stable.(93b) Digoxin (170) is a substrate of both intestinal and renal P-gp and coadministration of drugs that inhibit P-gp can quickly lead to the accumulation of this compound to toxic levels since the drug has a narrow therapeutic index. Because of these potential drug–drug interactions, medication with 170 requires close and careful monitoring.
Phlorizin (172), an O-aryl glycoside natural product found in several fruit trees including apple, cherry, and pear, is a nonselective sodium–glucose-linked transporter-2 (SGLT2) inhibitor that suffers from poor metabolic stability due to its susceptibility to degradation by β-glucosidases in the digestive tract which releases the aglycone phloretin (173), a well-known antioxidant widely used in skin care but which is inactive toward SGLT2 (Scheme 9).(94) While extensive SAR studies were being undertaken to identify analogues of 172 with improved metabolic stability and high selectivity for the SGLT2 transporter, WAY-123783 (174), a nonglycoside pyrazole derivative, was found to demonstrate an antihyperglycemic effect in the db/db mouse model of type II diabetes.(95−97) The pharmacological effect associated with 174in vivo was traced to the formation of the O-glycoside metabolite 175, a compound that was a 3-fold more potent inhibitor of SGLT2 than 172 (Scheme 10).(96,97) However, 175 exhibited only 7-fold selectivity for SGLT2 compared to SGLT1, but this could be enhanced to 180-fold by simply replacing the CH3S substituent on the phenyl ring with an isopropoxy moiety to afford 176. Despite its favorable metabolic stability in a rat intestinal assay and HLM, 176 showed virtually no oral bioavailability in rats (F = 0.4%), which was attributed to its poor membrane permeability (Caco-2 Papp = 1.02 × 10–6 cm s–1) resulting from the presence of 5 H-bond donors (HBDs). To reduce the number of HBDs, the nitrogen atom of the 1H-pyrazole heterocycle was substituted with a range of small alkyl groups from which the N-isopropyl analogue 177 was conspicuous as a potent and selective SGLT2 inhibitor with improved membrane permeability (Caco-2 Papp = 3.16 × 10–6 cm s–1), which contributed to a moderate increase in oral bioavailability (F = 3.2%).(98) To further improve membrane permeability and potentially enhance the intestinal stability of the glucosidic linkage, the 6-hydroxyl group of the glucose moiety was converted to its ethyl carbonate, leading to the discovery of remogliflozin etabonate (178) as a prodrug that exhibited a further increase in oral bioavailability (F = 5.8% in rats; Caco-2 Papp = 4.29 × 10–6 cm s–1).(98) Because of the potency and high selectivity over SGLT1 observed with 177, the carbonate prodrug remogliflozin etabonate (178) was selected for clinical evaluation. Following oral administration, 178 was rapidly absorbed (tmax = 0.5 h; t1/2 = 0.39 h) and deesterified by nonspecific esterases present in mucosal cells of the GI tract to release 177 (tmax = 0.64 h; t1/2 = 1.57 h), which underwent N- and O-dealkylation to give the major active metabolite 176 (tmax = 1 h; t1/2 = 2.68 h) along with small amounts of the inactive 179 (tmax = 1 h; t1/2 = 2.84 h), respectively.(98b,99) Unfortunately, the short plasma t1/2 values of 177 and its active metabolite 176 necessitate a BID dosing regimen, a disadvantage over other SGLT2-inhibiting drugs (QD dosing, t1/2 ≈ 12 h).(99a) Nevertheless, 178 was recently approved in India as a treatment for type 2 diabetes mellitus.(99b)

Scheme 9

Scheme 9. Metabolism of Phlorizin (172) to Phloretin (173) in Vivo

Scheme 10

Scheme 10. Metabolism of 174 to the Glucoside 175 in Vivo
While O-glycosides such as 178 showed reduced glucosidase-mediated degradation and enhanced systemic exposure compared to 172, their poor pharmacokinetic properties prompted further study of SGLT2 inhibitors, which were directed toward C-glucoside derivatives (vide infra).(97)

Fluorinated Thromboxane A2 Ligands

A very effective illustration of the stabilizing effect of electron-withdrawing substituents on acetal stability is provided by the natural product thromboxane A2 (TxA2, 180), which has been the subject of considerable attention due to its central role in a number of pathological states, including angina, thrombosis, and asthma.(100) TxA2 (180) is structurally unique because of the bicyclic acetal motif in which one of the oxygen atoms is part of an oxetane ring, a strained functionality that undergoes facile hydrolytic cleavage at pH 7.4 (t1/2 = 30 s), inherent chemical reactivity that controls the physiological half-life of the molecule. However, the chemical stability of the reactive oxetane acetal motif can be enhanced in a remarkable fashion by the introduction of one or two fluorine atoms into the oxetane ring, as demonstrated by 181-184.(101) For example, the t1/2 of TxA2 (180) at pH 7.4 was prolonged by 105 and 106 by mono- (181) and difluorine (182) substitution, respectively, and the bimolecular rate constant for the hydrolysis of the difluoro-substituted core scaffold 183 is reduced by 8 orders of magnitude compared to the parent molecule 180.(101a−c) The difluorinated core of 182 was combined with the urea β-side chain from known TxA2 antagonists to afford 184 which also functioned as a receptor antagonist. Another approach to improve the chemical stability is to expand the strained oxetane into a tetrahydrofuran ring, as demonstrated by homo-TxA2 (185), which showed no appreciable degradation when stored at −10 °C for 1 year.(101d)
The acetone-derived ketal ICI 180080 (186) was identified as a potent TxA2 antagonist, but chemical stability under acidic conditions was of concern in the context of oral drug delivery.(102) Replacement of the geminal dimethyl ketal substituents of 186 with an ortho-chlorophenyl (ICI 192605, 187) or a trifluoromethyl (ICI 185282, 188) substituent exerted a dramatic impact on the hydrolytic stability at pH = 2. Thus, 187 and 188 exhibited a t1/2 of 19.7 h and 7 years, respectively, compared to 56 s for the lead compound 186. Oral administration of 187 to anesthetized guinea pigs significantly inhibited the effects of a TxA2 agonist on pulmonary function for 6 h, suggestive of good metabolic stability.(102b) The mono-CF3 analogue 188 showed significantly enhanced stability with a t1/2 estimated to be 7 years at pH = 2 at 25 °C, a clear demonstration of the effect of an electron-withdrawing substituent on the hydrolytic sensitivity of acetals.(101a) In order to more fully characterize the stability of 188, studies were conducted at 91 °C where the anticipated hydrolysis of the cyclic acetal was observed to produce not only the triol 189 but also the diol 190. While the degradation rate of 188 declined as the pH increased, plateauing at pH = 5, instability was also observed at pH values beyond 6, where again both the triol 189 and diol 190 were identified as products, although both processes remained relatively slow even at 91 °C (10–6 s–1 at neutral pH and 10–4 s–1 at higher pH at 91 °C compared to 10–10 s–1 at neutral pH and 10–7 s–1 at higher pH at 25 °C). After a detailed kinetic analysis, the mechanism proposed to account for the formation of the diol is depicted in Scheme 11 and invokes the formation of a quinone methide intermediate, either 191 or 193, at both pH values, driven by deprotonation of the phenol (pKa ∼ 9) at high pH which affords 191, with acetal ring opening the rate-determining step.(102a) Reduction of the quinone methide by an intramolecular hydride transfer from the acetal methine would provide diol 192 in a process that requires a conformational change and rotation from the initially produced intermediate to relieve A(1,4) strain between the proton on the ortho position of the oxidized phenyl ring and the allylic substituent, thereby setting the stage for hydride transfer. A simple hydrolytic decomposition of the trifluoroacetic acid ester then leads to the diol 190. Under acidic conditions, 188 is proposed to degrade to the quinone methide 193, an intermediate that generates 194 after the loss of trifluoroacetaldehyde and then the observed triol 189 upon the addition of H2O (Scheme 11).(102a) These observations provide another example of the need to assess the chemical stability and potential degradation pathways of acetals and ketals holistically in the context of the overall structure and its relationship with proximal functionality.

Scheme 11

Scheme 11. Proposed Mechanism for the Hydrolysis of 188 at High pH Values

Fluoroartimisinins

Dihydroartemisinin (DHA, 196), which is the reduced form of artemisinin (195) and incorporates one ketal, one acetal, and one hemiacetal, is an effective antimalarial agent but suffers from a short t1/2 due to chemical instability and type II metabolism via the formation of water-soluble β-glucuronide derivatives which are conjugated at the hydroxyl of the hemiacetal moiety.(103,104) A CF3 substituent was introduced to the hemiacetal carbon to give 197 in a rational effort to increase hydrolytic stability and to reduce the propensity for glucuronidation, which can proceed by the two potential pathways summarized in Scheme 12.(103,105) In pathway 1 in Scheme 12, the CF3 group decreases the nucleophilicity of the tertiary hydroxyl group which renders 197 a poor glycosyl acceptor for 198. In pathway 2 in Scheme 12, the formation of the electrophilic carboxonium (carbonylonium) intermediate 200 is disfavored due to the high energy of this process as a result of the destabilizing effect of the CF3 substituent, which interferes with its reaction with glucuronic acid (201). Taken together, the CF3 substituent blocks both pathways of phase II metabolism, which results in a longer plasma t1/2 and improved oral bioavailability, which translates into enhanced oral activity in models of malaria.(103,105)

Scheme 12

Scheme 12. Potential Hydrolytic Degradation Pathways for 197
Artemether (202), the methyl ether derivative of 196, is another marketed antimalarial agent that also displays a short t1/2 due to the formation of 196 and the glucuronide 205 through either acid-mediated hydrolysis or CYP450-mediated oxidative demethylation via 204 (Scheme 13).(104,105) Once again, the introduction of the CF3 substituent in 203 not only enhanced hydrolytic stability and but also interfered with the oxidative metabolism pathway.

Scheme 13

Scheme 13. Metabolic Pathways for 202

1,3-Dioxane-2-carboxylic Acid Derivatives

Benzafibrate (206) is representative of a class of amphipathic carboxylic acid derivatives collectively described as fibrates that have been prescribed to treat a variety of metabolic disorders, including hypercholesterolemia.(106) These agents act by stimulating the peroxisome proliferator activated receptor-α (PPAR-α), but their agonist activity is weak and nonselective over other nuclear receptors.(107) In an effort to identify compounds with improved potency and selectivity, the conformational constraint of the oxyacetic acid terminus of the lead compound 207 was explored by the formation of the cyclic ketal 208, readily available synthetically by condensing the diol with methyl pyruvate.(108) In this process, the cis-isomer was either the exclusive product or the major isomer. The ester moiety of these dioxanes is known to preferentially adopt an axial orientation stabilized, in part, by a general anomeric effect (GAE) between the lone pairs of electrons on the ring oxygen atoms and the σ* orbital of the C–CO2Me bond.(109) The dioxane 208 was 100-fold more potent than 206 and exhibited greater selectivity over the related PPAR-δ receptor.(108) Methyl substitution of the phenyl ring enhanced both PPAR-α potency and selectivity over PPAR-δ with NS-220 (209), eliciting robust hypolipidemic activity in diabetic mice following oral administration.(108a) Further bioisosteric modification in which the oxazole was replaced with an oxime followed by insertion of a phenyl ring spacer in the alkylene chain led to the orally bioavailable, PPAR-α selective agonist 210 that exhibited superior pharmacokinetic properties.(110) Following oral administration, both 209 and 210 demonstrated antihyperglycemic activity in mouse models of diabetes and antihyperlipidemic effects in rats fed a high cholesterol diet. However, 210 appeared to be much more potent than 209 in both models due to better pharmacokinetic properties (t1/2 = 14 h vs 2 h in rats 30 mpk, PO).(110a)

Morpholine Acetals

A useful and effective strategy to stabilize acetals and ketals is to install a proximal basic amine, as exemplified by the selectivity observed in the acid-catalyzed degradation of the macrolide antibiotic clarithromycin (169) to give the desosamine derivative 211, as depicted inScheme 14. Protonation of the dimethylamine of the desosamine moiety retards additional protonation of the proximal glycosidic oxygen atom, thus enhancing the resistance of the carbohydrate moiety to acid-mediated degradation.(90,111) In contrast, the C3 cladinose glycoside, which lacks a basic amine, is susceptible to hydrolysis.

Scheme 14

Scheme 14. Acid-Mediated Degradation of 169
Although a morpholine heterocycle is only moderately basic (the conjugate acid of morpholine has a pKa value of 8.5, which is 2.6 units lower than for piperidine), it can function to stabilize acetals and ketals. Consequently, morpholine-based acetals have found utility in drug design, with the first application reported in 1996 as part of a search for orally bioavailable NK1 antagonists.(13,112−115) The lead piperidine-based NK1 antagonist 212, although quite potent, suffered from poor oral bioavailability and exhibited a modest affinity for the L-type calcium channel, a potential liability for adverse cardiovascular effects.(114) To address both issues, a significant effort was expended to reduce the basicity of the piperidine nitrogen atom, with two approaches proving to be effective: attachment of an electron-withdrawing heterocycle to the piperidine nitrogen atom linked through a methylene spacer and the introduction of an oxygen atom into the piperidine ring, a molecular edit that led to a morpholine acetal. Both approaches produced compounds with lower basicity than the lead prototype, and as anticipated, these compounds showed only negligible binding affinity for the L-type calcium channel, as exemplified by 213 and 214. When compared with the original piperidine, the morpholine acetal nitrogen of 214 is weakly basic with a measured pKa value of less than 3 in aqueous MeOH compared to 5.3 for the piperidine nitrogen, suggesting that morpholine protonation may play a limited role in enhancing the acid-sensitive stability of the acetal moiety. The reduced basicity of 214 contributed to a 4-fold enhancement in oral activity in the mammalian tachykinin substance P (SP)-induced dermal inflammation (SPIDER) assay in guinea pigs (ID50: 0.009 vs 0.037 mpk for 213).(13) The two major metabolic soft spots of 214 were determined to be cleavage of the benzyl ether and hydroxylation of the phenyl ring, which were blocked by α-methylation of the benzyl group and para-fluorination of the phenyl ring, respectively, to give aprepitant (21), which was approved by the FDA in 2003 to help prevent the nausea and vomiting associated with cancer drug therapy.(13) Aprepitant (21) is prescribed for oral dosing, while the somewhat unusual water-soluble N-phosphoryl prodrug, fosaprepitant (215),was developed for intravenous use.(115) The high stability of morpholine acetals under aqueous acidic conditions is exemplified by studies conducted with 214.(114a) After incubation of 214 in simulated gastric acid at 37 °C for 4 h, neither hydrolysis of the benzyl ether nor isomerization to the trans diastereomer was observed. The stability of 214 toward acid in the GI tract was confirmed by its potent activity in the SPIDER assay following oral dosing to guinea pigs.(114a)
An X-ray cocrystal structure of 21 bound to the NK1 receptor revealed that the exocyclic acetal oxygen atom adopted an axial orientation and interacted as a H-bond acceptor with the side chain amide N–H of Gln165 of the protein (Figure 5A and Figure 5B).(114c) The triazolone oxygen atom engaged in a bifurcated binding interaction with the acid moiety of Glu193 and the NH of Trp184. In the single-crystal X-ray structure of 21, the benzyloxy moiety was also axially disposed, a conformation that minimizes steric strain with the proximal fluorophenyl ring at the 2-position of the morpholine heterocycle while taking advantage of the energy advantage offered by the anomeric effect (Figure 5C).(114d)

Figure 5

Figure 5. A. Key H-bonding interactions between 21 and the NK1 receptor. B. Conformation of 21 bound to the NK1 receptor. C. Single-crystal X-ray structure of 21 (GOPDUK, deposition number 117932 in the CSD).(114c,d)

The discovery of the γ-secretase modulator SPI-1965 (218) as a clinical candidate was highlighted by the replacement of a pendent native sugar of the triterpene glycoside 216 with a morpholine acetal to afford 217.(116) The sugar moiety of 216 contributed to the high TPSA of 155 Å2, a property that strongly correlated with poor CNS permeability. Replacement of the sugar element with a morpholine acetal reduced the TPSA by 32%, leading to significant improvement in both brain penetration and oral bioavailability for 217. Optimization of the morpholine side chain and transformation of the acetate to an ether afforded 218, which is orally bioavailable, brain penetrant, and efficacious at lowering Aβ42 levels in multiple rodent models.(116) In the single-crystal X-ray structure of 218 depicted in Figure 6, the exocyclic oxygen atom of the morpholine acetal adopts an equatorial disposition.(116d)

Figure 6

Figure 6. Single-crystal X-ray structure of 218 (QESQIR, deposition number 1817710 in the CSD).(116d)

Transformation of the native sugar in the antifungal agent sordarin (219) into a morpholine acetal was also explored as an approach to the discovery of semisynthetic analogues with oral bioavailability.(117) Because of its weak antifungal activity and poor pharmacokinetic profile, 219 exhibits only marginal activity in in vivo models of infection. Utilizing morpholine or homomorpholine as a replacement for the glycoside maintained or even increased antifungal potency. Further optimization of the headgroup provided the semisynthetic derivatives 220223, which displayed superior antifungal activity compared to 219 and enhanced pharmacokinetic properties, with the homomorpholine derivative R-135853 (222) exhibiting 63% oral bioavailability in mice that translated into good oral efficacy in rodent models of fungal infection.(117e)
A weakly basic morpholine acetal was recently exploited as an approach to enhance the brain penetration of a series of BACE1 inhibitors originating from the prototype 224.(118) In this example, both the piperidine in 224 and the morpholine in 225 adopt a similar chair conformation, as revealed by NMR and X-ray crystallographic studies. However, the switch from the piperidine ether 224 to the morpholine acetal 225 increased brain exposure by 5-fold due to the reduced basicity of the core heterocycle, while replacing the cyclohexyl with a tert-butyl further improved both cellular activity and brain penetration in the context of 226.(118) In the cocrystal structure of 226 with the BACE1 enzyme, the exocyclic oxygen atom of the morpholine acetal and the methyl substituent bound to the adjacent carbon atom adopt axial orientations, while the hydroxyethylene bioisostere element is equatorially disposed, consistent with the conformation observed in solution based on NMR studies (Figure 7). The anomeric effect favors the bound conformation of 226, and neither of the oxygen atoms of the morpholine acetal moiety appear to be engaged directly in drug–target interactions.

Figure 7

Figure 7. Conformation of 226 when bound to BACE1 (Protein Data Bank 6BFX).(118)

5-Amino-1,3-dioxanes

2,5-Disubstituted-1,3-dioxanes exhibit a preference for an axial disposition of polar substituents at the 5-position, although the conformational disposition can be dependent on the solvent, as summarized in Table 6 where data are collated for multiple solvents only where a dependence was observed.(119) Notably, protonated amine and trimethylammonium substituents exhibit a strong preference for an axial orientation (entries 1–3) as do NO2, CH3SO2, and CH3SO (entries 4–6) while the nonpolar CH3S prefers to adopt an equatorial disposition (entry 7). In the halogen series (entries 8–10), only fluorine prefers an axial orientation while the disposition of CN (entry 11) is solvent-dependent. The CO2CH3 moiety, carboxylate anion, OCOCH3, OCH3, OCH2CH3, and CH2OCH3 (entries 12–18) all prefer equatorial orientations while the disposition of CH2OH (entry 19) shows solvent-dependence. These preferences have been attributed to the electrostatic attraction between the substituent and the ring oxygen atoms.(119)
Table 6. Energy Differences between the cis- and trans-Isomers of Substituted Dioxanes that can Equilibrate under Acidic Conditions
5-Amino-1,3-dioxane derivatives offer interesting physicochemical properties that were first appreciated by medicinal chemists in 1999 as part of a study of orally bioavailable somatostatin receptor (SSTR) agonists for the treatment of acromegaly, a disorder that is the result of excessive growth hormone release by the pituitary gland.(120) The lead compound in the series, lysine derivative 227, was a potent SSTR-2 agonist but lacked oral bioavailability due to poor absorption. The 5-amino-1,3-dioxane ring in 228 was incorporated as a lysine surrogate, thus eliminating the ester moiety while also reducing the basicity of the primary amine. This molecular edit improved aqueous solubility and oral absorption, which contributed to superior oral bioavailability. However, SSTR-2 agonist activity was reduced by 4-fold but could be restored by introducing a second phenyl ring to the side chain, as in 229, which led to an additional enhancement of oral bioavailability.(120)
More recently, this amino acetal moiety has been incorporated into G-5555 (232), a selective PAK1 kinase inhibitor examined for its potential to treat cancer and other diseases.(2) The combination of a basic amine and high lipophilicity in the lead compound 230 led to significant inhibitory activity toward ion channels, including the human ether-à-go-go-related gene (hERG) cardiac potassium channel, while poor membrane permeability was an additional concern. It is known that hERG ion channel liability can often be attenuated by either reducing basicity or lowering lipophilicity. The replacement of two methylenes in the cyclohexane of 230 with oxygen atoms to form an acetal simultaneously addressed both concerns: the calculated pKa (cpKa) of 10.4 for 230 was reduced to 7.7 in the prototype 231, while the cLogP value declined from 4.5 to 2.4. The combination of effects resulted in a 5-fold reduction in hERG inhibitory potency and a 4-fold enhancement in membrane permeability. Further optimization delivered G-5555 (232) as a potent and orally bioavailable PAK1 kinase inhibitor with only negligible hERG inhibition. The acetal functionality in these compounds was shown to be stable under acidic conditions at pH 1 for 24 h at room temperature.(2)
A cocrystal structure of 232 in complex with PAK1 kinase showed that the 5-amino-1,3-dioxane ring adopted a chair conformation in which both substituents were equatorially disposed, a topographical arrangement that allowed the amine to engage in H-bonding interactions with the backbone carbonyl of Asp393 and a H2O molecule, the latter a bridge to the side chain C═O moiety of Asn394. The alternative conformation would place both substituents in an axial orientation which can, in some circumstances, be favored for amine, stabilized by electronic effects and the potential for intramolecular H-bonding interactions to the ring oxygen atoms, as depicted in the alternate conformation.(119) The conformation of 232 in the cocrystal presumably reflects the spatial arrangement necessary for the amine to engage in H-bonding interactions with the PAK1 enzyme.(2)
A similar strategy has recently been adopted to reduce the hERG ion channel inhibition observed in a series of novel bacterial type II topoisomerase inhibitors (NBTIs) investigated as antibacterial agents.(121) In this example, the hERG inhibition associated with the dioxane-linked compounds 233 and 235 was 20-and 10-fold less potent than the corresponding cyclohexane-linked analogues 234 and 236, respectively. Replacement of the basic secondary amine in 235 with a secondary carboxamide (237) further reduced hERG inhibition while maintaining potent inhibitory activity toward S. aureus. Finally, installation of a 3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide heterocycle to replace the 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide moiety of 237 afforded 238, a potent NBTI and antibiotic agent with MIC values of 0.125 μg/mL toward both methicillin-susceptible (MSSA) and -resistant (MRSA) S. aureus.(121b) However, detailed chemical stability studies and the in vivo performance of these compounds have not been described.
While 2-alkyl-1,3-dioxan-5-amines have been shown to demonstrate resilience toward acid hydrolysis, a 2,2-dialkyl-1,3-dioxan-5-amine has been utilized as a prodrug moiety in 240, which releases the parent amino diol fingolimod (FTY720, 239) in the mildly acidic environment of endosomes where the pH is ∼5.0.(122) This prodrug concept was designed to avoid systemic phosphorylation of 239 to its active metabolite which causes immunosuppression by activating the sphingosine-1-phosphate receptor 1 (S1P1) but which is also associated with lymphopenia and bradycardia. The introduction of the polyethylene glycol (PEG) moiety enhanced the aqueous solubility of the prodrug, which is taken up by cancer cells where 239 is released in the endosomal compartment and induces metabolic stress.(122) The potential of the prodrug 240 to release 239 was assessed by incubation at 37 °C in 10 μM deuterated acetate and tris buffers at pH 5.0 and 7.4, with prodrug integrity followed by 1H NMR. At pH = 5, 80% of prodrug 240 had degraded to release 239 after 28 h of incubation while the molecule was completely stable at the physiological pH of 7.4. This observation was interpreted based on the change from a hydrophobic molecule to one that is more hydrophilic upon protonation.(123) In this case, the presence of the amine facilitates hydrolysis, which appears to be inconsistent with the internal protection concept of the amine in the amino acetal, as in compound 232. However, in this case, the acid sensitivity may be promoted by the protonated primary amine substituent preferentially adopting an axial conformation that facilitates activation of the ketal toward hydrolysis by engaging the oxygen atoms in an intramolecular H-bonding interaction.(119) Nevertheless, additional studies are needed in order to more fully understand the factors that have an impact on the acid stability of these amino acetal- and amino ketal-based systems.
While the stability of the 5-amino-1,3-dioxane moiety toward acidic hydrolysis can be modulated by the presence of the mildly basic amine, which will more readily accept a proton than the acetal moiety, a basic moiety is not an essential prerequisite for oral bioavailability.(124) A series of carbamates derived from a 2-phenyl-1,3-dioxan-5-amine core scaffold 241, represented by 242 and 243, has been shown to demonstrate efficacy in a xylene-induced ear edema mouse model of inflammation following oral administration.(124) These cyclic acetals did not function as prodrugs since the corresponding aldehydes and aminodiols were inactive in the respective animal studies. In this series, biological activity was found to be independent of the relationship between the dioxane substituents, with both the cis- and trans-isomers effective in vivo, as exemplified by 241 and the comparison between 242 and 243. In these molecules, the C5 amine and carbamate functionalities are oriented in axial conformations regardless of the relative configuration of the phenyl substituent at C2. In the case of 242 and 243, a hydrogen-bonding interaction between the carbamate NH and the heterocyclic oxygen atom may additionally contribute to the stability of the axial conformer.
Another interesting example of the stability of a nonbasic 5-amino-1,3-dioxane moiety toward acid hydrolysis is provided by the maleimide-based linkers 244247 explored for application in the design of antibody–drug conjugates (ADCs) where a replacement for the hydrophobic cyclohexane in 248 was sought to improve aqueous solubility.(125) The stability of these moieties to hydrolytic degradation was assessed in the context of the series of fluorescence resonance energy transfer (FRET)-based probes 244248 compiled in Table 7. In these molecules, the fluorescence of the tetramethylrhodamine (TAMRA) fluorophore is quenched by the proximal BHQ element when intact, but rupture of the molecule will lead to an increase in fluorescence. Incubation of these molecules at pH values ranging from 2 to 9 in buffers resulted in no more than a 10% increase in fluorescence, reflective of excellent stability under these conditions, thus meeting the criteria of a noncleavable linker. Degradation was only observed under the strongly acidic conditions associated with aqueous 1 M HCl, with the rates compiled in Table 7.(125a) The 1,3-dioxane linker provided slightly better chemical stability than the homologous dioxolane (compare 246 with 244 and 247 with 245) which can be attributed to the effects of the ring size of the cyclic acetal.(15i,17c) The dioxane 244 exhibited comparable stability to the cyclohexane prototype 248 in human plasma and in a variety of aqueous buffers, while the dioxolane 246 was slightly less resistant to degradation. However, the rupture of these molecules to produce fluorescence is complex, with a retro-Michael addition of the thiol to the maleimide moiety a potential contributor. While the detailed comparison between 244 and 248 revealed the superiority of the former, some of the advantages were attributed to more facile ring opening of the maleimide moiety in 244, which would stabilize the molecule toward a retro-Michael elimination of the BHQ-2 thiol element and preserve fluorescence quenching.(125a) This is presumably a function of the less basic amine embedded in 244 compared to 248, which facilitates imide hydrolysis.
Table 7. Measured Rate Constants for the Degradation of the Series of FRET-Based Probes 244248 under Acidic Conditions

Basic Heterocycle-Containing Acetals and Ketals

In addition to basic amines, mildly basic heteroaryl rings can also contribute to enhancing the stability of proximal acetals. Two well-known examples are provided by the antifungal agents ketoconazole (249) and itraconazole (250), which exhibit good to excellent oral bioavailability in humans.(126−128) Ketoconazole (249) was the first orally bioavailable, broad-spectrum antifungal medication licensed, but the oral tablet has been discontinued in many countries due to the potential for this drug to cause severe but idiosyncratic liver damage, which has been attributed to metabolic activation of the piperazine ring which generates an aldehyde intermediate.(129) Ketoconazole (249) is also a potent human CYP3A4 inhibitor that can alter the serum levels of many drugs including macrolide antibiotics that are metabolized by CYP3A4, thus increasing the toxicity of these agents.(130) The CYP3A4 inhibition associated with 249 is attributed to the imidazole ring, which coordinates the Fe atom of the enzyme. Replacement with a triazole led to second-generation antifungal azoles including 250, which has shown a better safety profile and an expanded spectrum of activity, although potent CYP3A4 inhibition remains a problem.(128) The major site of metabolism of 249 is by N-deacetylation to afford 251 while for 250 it is oxidation to give hydroxyitraconazole 252.(131,132) Metabolite 253, which arises from dioxolane ring cleavage, was also detected in urine samples obtained from patients taking 250.(132b)
The discovery of 249 has its origins in a survey of analogues of miconazole (254), the first member of the conazole family, that was used primarily for the topical treatment of fungal infections.(133,136) The synthetic protocol under study employed 2-(imidazolyl)-acetophenone (255) as a starting material which was protected as the ethylene ketal 256 to facilitate further chemical transformations.(134) Surprisingly, the ketal intermediate 256 exhibited a broad-spectrum antifungal activity, an observation that prompted the synthesis of more complex dioxolanes that incorporated a substituent on the diol moiety. This exercise led to the discovery of 257, which cured C. albicans-infected animals in a rat model of vaginal candidiasis, and 258 and 259, which cured guinea pigs of a cutaneous C. albicans infection after oral doses of 10 mpk.(135) However, while none of these compounds were effective in both infection models, the incorporation of an oxygen atom in the side chain moiety resulted in the identification of the phenoxymethyl ketals 260 and 261, which demonstrated superior oral efficacy in effecting cures in both models of fungal infection.(136) Subsequently, a piperazine moiety was added to the side chain to improve both solubility and oral absorption, an effort that culminated in the discovery of 249.(127)
The biochemical target of 249 is the enzyme 14-α-sterol demethylase, a CYP450 monooxygenase of the CYP51 gene family that converts lanosterol to ergosterol, a constituent of fungal cell membranes.(131a) Docking studies of 249 within the active site of CYP51 suggested that there were no direct H-bonding interactions between the ketal oxygen atoms and the enzyme, but the cyclic ketal played an important role in orientating the imidazole group directly above the central heme iron atom with a distance of 3.458 Å between the sp2 nitrogen of the imidazole and the catalytic Fe atom.(137) In this bioactive conformation, the 2,4-dichlorophenyl ring engaged with the side chain of Phe134 via a π–π stacking interaction while His381 is able to donate a H-bond to the side chain oxygen atom of 249. In addition, the two ketal oxygen atoms of ketoconazole contribute to its favorable lipophilicity (cLogP = 3.6), which translated into superior oral absorption and oral bioavailability when compared to the more lipophilic 254 (cLogP = 5.8).
SB203580 (262) is a selective p38α mitogen-activated protein (MAP) kinase inhibitor explored for its potential to treat rheumatoid arthritis; however, this compound exhibited modest oral bioavailability, induced chromosomal damage, and inhibited CYP1A1.(1,138) To address these issues, the phenyl ring at the 2-position of the imidazole, which binds in the same region as adenosine triphosphate (ATP), was replaced with a cyclic acetal, leading to the identification of two compounds, 263 and 264, with good oral bioavailability and oral efficacy in a rat model of the streptococcal cell wall (SCW)-induced arthritis.(1,138) The synthetic protocol produced a mixture of isomers which were separated by chromatography and the identities of individual compounds assigned based on the assumption that the diarlyated imidazole would adopt an equatorial disposition on the dioxane ring. These acetal analogues were found to be highly resistant to acidic, basic, and oxidative conditions, which may be attributed to the mild basicity associated with the imidazole ring and/or the modest electron-withdrawing effects associated with the 2-position of the heterocycle, which would help to destabilize the positively charged intermediates that arise during hydrolysis.(139) This approach to stabilizing acetals and ketals, which has found only limited application in medicinal chemistry, was extended within this series of p38α MAP kinase inhibitors to include the azoles 265268, which are advantageous based on their reduced lipophilicity and increased fraction of saturated carbon atoms (Fsp3) compared to the phenyl ring homologues.(47,140,141)
RP70676 (269) was identified as a potent orally bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis, but it underwent rapid metabolism to give two enantiomeric sulfoxides, of which only the (S)-(−)-isomer RP73163 (270) showed moderate ACAT inhibition while 271 was inactive.(142) This prompted a study directed toward replacing the sulfoxide linkage with a conformationally restrained group, preferably a heterocycle, which would maintain the imidazole and pyrazole elements in their bioactive conformation and enhance potency. As the first step in that process, a number of simple 2-substituted 4,5-diphenyl-1H-imidazole derivatives 272-276 were evaluated to determine the optimal minimal pharmacophore required to maintain inhibitory activity. This survey revealed that the preferred 2-substituents were the six-membered rings 1,3-dioxan-2-yl (272), tetrahydropyran-2-yl (274), and phenyl (276). However, the lipophilicity of 276 was a concern for solubility and oral absorption, while the tetrahydropyran-2-yl substituent in 274 introduces the complication of a chiral center which would mean that rapid SAR expansion would be a challenge. As a result, the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole moiety 272 was selected as the vehicle for further optimization because of its potent inhibitory activity, desirable lipophilicity, and facile synthetic accessibility. Chemical lability toward hydrolysis was judged to be of limited concern based on the presence of the moderately basic imidazole heterocycle. Both cis- and trans-disposed compounds were isolated, with 1H NMR data suggesting that the dioxane ring system adopted a chair conformation with the bulky 4,5-diphenyl imidazole moiety oriented equatorially.(142) The CH2 protons of the axial hydroxymethyl substituent of the cis-isomer 281a encountered 1,3-diaxial interactions with the lone pairs on the oxygen atoms, thus resonating downfield when compared with the trans-isomer 281b in which this group is equatorial (3.86 vs 3.41 ppm) (Figure 8). A similar downfield effect was observed with the methyl group of the trans-isomer (1.25 vs 0.8 ppm). In this example, the chair conformation of the dioxane ring system provides a useful scaffold on which to deploy substituents with good stereochemical control. The cis disposed 277 (IC50 = 75 nM) was more potent than the trans-isomer 278 (IC50 = > 500 nM). Further optimization led to the water-soluble compounds 279 (IC50 = 60 nM) and 280 (IC50 = 70 nM). When dosed orally at 10 mpk in rats, 279 and 280 produced plasma concentrations of 1.3 μM and 2.2 μM, respectively, at 90 min post dose, 20- and 30-fold higher than their IC50 values for ACAT inhibition in macrophages.(142) Both compounds were considered as potential candidates for development as oral therapeutics for the treatment of atherosclerosis.

Figure 8

Figure 8. 1H NMR data for the substituted dioxanes 281a/b.

Oxapadol (282) is a non-narcotic analgesic that demonstrated activity in models of pain conducted in mice, rats, and rabbits, providing the basis of advancement into clinical trials which occurred in the late 1970s.(143) SAR studies indicated that the dioxolane ring and its relationship and connectivity with the benzimidazole were of importance to the expression of pharmacological activity, which was assessed by screening for analgesic activity in mice as protection against phenylbenzoquinone-induced writhing.(143a) While 282 appears to have been advanced as a racemic mixture, the (1R,4S)-isomer 283 was more potent than the (1S,4R)-enantiomer 284 with ED50 values of 30 and 100 mpk, respectively. In a placebo-controlled trial conducted in 10 medical students, 282 was evaluated for its ability to attenuate the nociceptive reflex in the lower limbs in response to an electrically induced stimulus. Oral doses of 600, 800, and 1000 mg of 282 were associated with an increase in the nociceptive threshold at time points after drug ingestion ranging from 30 to 180 min, with the effect at all doses reaching statistical significance compared to placebo.(144a) Oxapadol (282) was extensively metabolized following oral dosing to rats, dogs, and humans with no unchanged drug detected rat and human urine and just trace amounts in dog urine.(144b) A total of nine metabolites were identified that reflected hydroxylation of the benzimidazole ring and cleavage of the dioxane-containing heterocycle moiety, with phenol metabolites dominant in humans and amounting to 40% of the radioactivity in urine while N-dealkylation to give 286 and 287 was observed in rats and dogs but not humans. Acid-mediated dioxolane hydrolysis in the gut was considered as a possible contributor to the fate of the molecule in vivo since incubation of 283 at pH = 2 and 37 °C resulted in slow hydrolysis to afford 285, one of the identified metabolites, although 93.5% of the parent remained after 120 min of incubation suggesting this pathway to be of low significance (Scheme 15).

Scheme 15

Scheme 15. Acid-Catalyzed Degradation of 282 to afford 285 and the N-Dealkylation Metabolic Pathway Observed in Rats and Dogs to Afford 286 and 287

Bicyclic Acetals and Ketals

Bicyclic acetal/ketal or hemiacetal/ketal motifs in which the oxygen atoms are in the same ring are ubiquitous in carbohydrates and natural products, and both topologies offer increased resistance to acid-mediated hydrolytic decomposition because the formation of the acetal or ketal is a fast and thermodynamically favored intramolecular process. Acetalizaton and ketalization of this type offer a straightforward and sometimes readily accessible approach to conferring conformational rigidity while introducing polarity, which can translate into enhanced biological and pharmaceutical properties.(145)

Bridged Acetals

Since O-glycosides like phlorizin (172) are limited by poor pharmacokinetic properties (vide supra), extensive study has been devoted to the development of analogues with improved metabolic stability and improved oral bioavailability, culminating in the discovery of canaglifozin (288) and dapagliflozin (289), C-aryl glucosides which were approved by the FDA in 2013 and 2014, respectively, for glycemic control in adults with type 2 diabetes.(146,147)
An overwhelming majority of the continued efforts on C-aryl glucosides have focused on the aglycone side chain due to the pharmacophoric requirements associated with the sugar ring and the relatively straightforward chemical transformations available to modify that element.(148) However, one modification to the glucoside moiety that has been examined is through a novel cyclization strategy that establishes a link between C1 and C5 using a CH2O bridge.(149) When this transformation was implemented in the background of 289, ertugliflozin (290) was identified as an SGLT2 inhibitor that displayed improved inhibitory activity and selectivity over SGLT1 (Figure 9).(149) This compound exhibited low plasma clearance in rats and dogs, with t1/2 values of 4.1 and 7.6 h, respectively, while oral bioavailability was 69% in rats and 94% in dogs. In humans, 290 exhibited 100% oral bioavailability and a terminal elimination t1/2 in the range of 11–18 h, which supported a QD dosing regimen.(150)In vitro biotransformation studies with 290 in liver microsomes and cryopreserved hepatocytes from rats, dogs, and humans revealed no evidence of ketal cleavage.(150a) The discovery of 290 is an interesting example of the role of innovative chemistry as an integral part of modern drug discovery, further illustrated by the observation that the alternate 1,5-linker topology in iso-ertugliflozin (291) affords a compound that is over 800-fold less potent.(149,151)

Figure 9

Figure 9. Design principles that led to the discovery of 290.

More recently, this 1,5-cyclization strategy has been extended to the thiomethyl xyloside core of sotagliflozin (292), a dual SGLT1 and SGLT2 inhibitor that is approved in Europe for the treatment of type 1 diabetes mellitus.(152) In this case, cyclization to give 293 reduced the SGLT2 potency by nearly 10-fold, but replacing the thiomethyl substituent with a methoxy afforded HSK0935 (294), which restored SGLT2 inhibitory potency while simultaneously increasing selectivity over SGLT1 inhibition.(153) Overall, in this context 1,5-cyclization of 292 transformed a dual inhibitor into a selective SGLT2 inhibitor, and 294 is currently undergoing preclinical development for the treatment of type 2 diabetes.
The enzyme 5-lipoxygenase (5-LO) enzyme metabolizes arachidonic acid and plays an important role in the production of leukotrienes which cause inflammation in asthma, allergic rhinitis, and osteoarthritis, providing the basis for interest in the discovery of 5-LO inhibitors as antiinflammatory agents.(154) L-702,539 (295), a tertiary alcohol derivative, was identified as a selective and moderately potent 5-LO inhibitor but was the subject of extensive oxidative metabolism, with 296299 identified as inactive metabolites that amounted to 6–7% after 1 h incubation in RLM (Figure 10).(155a) The two major metabolic soft spots were the lactone and the tetrahydropyran ring, with the former affording the hydroxylactone 296 while the latter generated the hydroxypyran 297, which was further oxidized to the hydroxy acid 298, a metabolite also in equilibrium with lactone 299 (Figure 10). To block α-hydroxylation on the tetrahydropyran ring, both positions were substituted with a bridging moiety that created the oxabicyclooctane analogue 300, a compound associated with fewer metabolites than the prototype in the plasma following oral dose to rats. However, 300 was 3-fold less potent than 295 in both a human 5-LO and a human peripheral blood polymorphonuclear monocyte (HPMN) assay and 7-fold less active in a human whole blood (HWB) assay, which was attributed to the increased protein binding due to higher lipophilicity (cLogP = 4.8 for 300 compared to 4.3 for 295). Transformation of the oxabicyclooctane core in 300 into a dioxabicyclooctane homologue 301 reduced the cLogP from 4.8 to 4.1, which translated into a 2-fold enhancement in potency in the HWB assay (IC50 = 540 nM compared to 1 μM for 300). More importantly, incorporation of the second oxygen atom in the ring to form a cyclic acetal led to improved metabolic stability with only 1–2% of the molecule metabolized by RLM over 1 h of incubation. Thus, the dioxabicyclooctane bicyclic ring system was established as a metabolically stable surrogate of a tetrahydropyran ring, and 301 was subjected to additional optimization by phenyl ring modification which identified the 3-furyl analogue 302 as a compound comparable to 295 in both the human 5-LO and HWB assays. After oral administration of 302 to rats, no major metabolites were detected with the exception of the expected hydroxylactone. Hydroxylative metabolism of the lactone moiety was addressed by replacement with a nitrile which furnished 303, a compound that generated only a single metabolite in RLM that amounted to just 0.4% of material after 1 h of incubation. The strong resilience to oxidative metabolism was also demonstrated in vivo with no major metabolites observed after oral studies in rats at a dose of 20 mpk.(155a) Nevertheless, further development of 303 was hampered by moderate potency and low oral bioavailability (10% in rats) due to limited oral absorption, which was ascribed to its high lipophilicity (cLogP = 4.1). Adding a nitrogen atom to the phenyl ring to provide the pyridine homologue 304 resulted in a 1.4 unit reduction in the cLogP value, which translated into a 2.5-fold increase in oral bioavailability in rats and a 2-fold improvement in Cmax in rat plasma (5 μM compared to 2.5 μM for 303, 20 mpk, PO).(155b) In contrast, the tetrahydropyran prototype 307 exhibited a much lower Cmax (2 μM), again demonstrating the potential of using the dioxabicyclooctane ring as a metabolically more stable bioisostere of tetrahydropyran. L739,010 (304) also presented a favorable pharmacokinetic profile in dogs with an oral bioavailability of 73% and an estimated half-life of 16 h. The pyridine analogue 304 was also significantly more active than the phenyl analogue 303 with HWB an IC50 of 42 nM and elicited robust oral efficacy in several animal models of asthma including a functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys. However, biotransformation studies in rat, dog, monkey, and human liver microsomes revealed oxidative cleavage of the furan moiety to the highly reactive 2-butene-1,4-dialdehyde derivative 305 as the major site of metabolism while hydroxylation of the unsubstituted dioxabicyclo moiety to give 306 was a minor pathway.(156) Development of 304 was discontinued presumably because of concerns associated with the metabolism of the furan ring into products capable of effecting covalent binding in vivo.(156)

Figure 10

Figure 10. Structure of the 5-LO inhibitor 295, metabolic pathways and structural evolution.

Spiroketals

A spiroketal core emerged as a design element that enforced the nearly perpendicular orientation between the glucoside and proximal phenyl of the aglycone observed in the lowest energy conformation of several SGLT2 inhibitors.(157) This spiro scaffold originated from the hit compound 309 that was identified from a search of the Cambridge Structural Database (CSD) in which a glucose core with two pendent aromatic rings, Ar-1 and Ar-2, was used as the pharmacophoric elements that were derived from an overlay of four SGLT2 inhibitors with the in-house C-naphthyl glucoside inhibitor 308 (Figure 11). An absence of promising lead structures necessitated an adjustment to the query, which relaxed the search to two pharmacophore elements, the glucose moiety and Ar-1 (Figure 11). This pharmacophore enquiry identified 309 as a molecule with promising structural overlap with prototype SGLT2 inhibitors notably 310, the core of dapagliflozin (289). Substitution of the 1,3-dihydroisobenzofuran in a fashion designed to mimic known SGLT2 inhibitors afforded 311 and 312 as representatives of a new C-aryl glucoside class of potent SGLT2 inhibitors. Analogues lacking the chloro substituent on the central phenyl ring exhibited superior potency and selectivity, with the 4-ethyl benzyl derivative tofogliflozin (314) superior to the 4-ethoxybenzyl homologue 313. Interestingly, the chlorinated compound 312 caused severe diarrhea in mice 6 h after a single oral dose of 25 mpk; however, the des-chloro counterpart 314 posed no toxicity issues.(158) When compared with 289, 314 showed comparable SGLT2 inhibitory activity with enhanced SGLT1 selectivity, as well as excellent oral bioavailability in mice (75%), cynomolgus monkeys (85%), and humans (98%).(157)

Figure 11

Figure 11. Design principle subtending the discovery of the core bicyclic ring system found in tofogliflozin (314).

The spirocyclic ketal 1,7-dioxaspiro[5.5]undecane 315 was designed as a conformationally restricted template to secure the disposition of the two key aromatic rings required for potent inhibition in a series of NK1 antagonists (Figure 12).(159a) The spiroacetal system in 315 exists exclusively in conformation 315a due to the anomeric effects, which are additively reinforcing since both C–O bonds in the spiro ring system are antiperiplanar to an oxygen lone pair, and 315 can thus be considered as a conformationally biased system. In terms of free energy, 315a is 2.27 kcal/mol lower than 315b, which benefits from only a single anomeric effect, and 4.54 kcal/mol lower than 315c. Based on molecular modeling, the (5S,6S,9S)-isomer of 315 offered the optimal orientation of the two aryl rings critical for recognition by the NK1 receptor while also providing the potential for a key hydrogen-bonding interaction between the oxygen atom at the 7-position and the receptor. Indeed, 316 (hNK1 IC50 = 28 nM) was significantly more potent than the (5S,6S,9R)- (44% inhibition at 1 μM), (5S,6R,9S)- (47% inhibition at 1 μM), and (5S,6R,9R)- (hNK1 IC50 = 400 nM) diastereomers (structures not explicitly shown). Optimization of 316 afforded 317 and 318, both of which demonstrated very high NK1 binding affinity and good CNS penetration, as measured by blockade of agonist-induced foot tapping in the gerbil following an IV dose.(159a) The [4.5]-spiroacetal analogue 319 exhibited hNK1 inhibitory potency comparable to 316, which was refined to 320, a potent hNK1 antagonist with good CNS penetration following IV dosing. However, the chemical stability and oral bioavailability of this series of NK1 antagonists were not described. The potential of this interesting spiroacetal scaffold remains to be further explored since this article is the only description of its application in structure-based drug design, although there are extensive studies on spiroacetal-based natural products with similar motifs.(159b−e)

Figure 12

Figure 12. Conformations available to 1,7-dioxaspiro[5.5]undecane (315).

Bis-THF and Tris-THF Moieties in HIV-1 Protease Inhibitors

A series of human immunodeficiency virus-1 (HIV-1) protease inhibitors incorporating a bis-tetrahydrofuran (bis-THF) as the P2 element was designed based on the X-ray cocrystal structure of saquinavir (321) bound to the enzyme, which revealed critical H-bonds between the P2-asparagine carbonyl and the backbone NH of Asp30 and the P3-quinaldic amide carbonyl and the backbone NH of Asp29 (Figure 13).(160) In the designed bis-THF ligand 322, both acetal oxygen atoms are optimally deployed to function as H-bond acceptors by simultaneously engaging the backbone NH’s of Asp30 and Asp29. The bicyclic acetal functionality is key for potent protease inhibitory activity since the two mono-THF analogues 323 and 324 are significantly less active, presumably a function of the loss of one of the H-bonding interactions. The bis-THF P2 moiety derivative possesses a lower molecular weight, fewer amide bonds, and reduced lipophilicity compared to 321, all of which contribute to improvements in solubility and oral bioavailability. Deploying the bis-THF P2 moiety on the structural background of amprenavir (325) led to the discovery of darunavir (326) as a conceptually new HIV-1 protease inhibitor with high potency and clinical efficacy toward resistant viral infections.(160) In this context, the bis-THF ring system mimics aspects of the sulfone moiety of 327 but with the advantage that the topographical disposition of the O atoms is such that it can engage both HIV-1 protease H-bond donors. Darunavir (326) is extensively metabolized almost exclusively by CYP3A4, and coadministration with small doses of the potent CYP3A4 inhibitor ritonavir increases its oral bioavailability from 37% to 82% in humans, although the dosing combination had a more modest effect on the PK profile in mice (2-fold), rats (4-fold), and dogs (no effect).(161) The major metabolites of 326 reflect carbamate cleavage, hydroxylation of the iso-butyl moiety, hydroxylation of the aniline ring, and small amounts of benzylic hydroxylation to afford an alcohol that is glucuronidated.(161) The bis-THF ring of 326 does not appear to be a site of metabolic modification, unlike in the progenitor 325, where dihydroxylation of the THF ring followed by ring opening was found to be a major metabolic pathway.(162) Darunavir (326) was approved by the FDA in 2006 for the treatment of HIV-1 infection and acquired immunodeficiency syndrome (AIDS), and it is on the WHO’s List of Essential Medicines.

Figure 13

Figure 13. Structure of HIV-1 protease inhibitor 321 depicting key intermolecular H-bonding interactions and evolution to bicyclic ethers.

More recently, expansion of this P2 element concept to the tris-THF homologue GRL-0519A (328) and crown ether-like THF derivative 329 has been explored, providing inhibitors with enhanced potency activity due to additional H-bonding or hydrophobic interactions (Figure 13).(163)

Peroxy Ketals (R–O–O–C–O–R′)

1,2,4-Trioxanes

The discovery of artemisinin (195) as a malaria therapy by over 500 scientists from 60 institutions across China in the 1970s represented one of the greatest advances in medicine in the 20th century.(164) Artemisinin (195), also known as qinghaosu, was isolated from leaves of the Chinese plant Artemisia annua (qinghao or sweet wormwood) and possesses an unprecedented structure that combines a sesquiterpene lactone with an embedded cyclic peroxy ketal and an acetal. Surprisingly and perhaps remarkably considering the structure, 195 exhibits unusual stability toward both heat and light. No appreciable decomposition occurs when 195 is heated at 150 °C in neutral solvents, which is just below its melting point of 156–157 °C, and the compound can be sublimed, while the neat solid survives heating at 200 °C, 50 °C above its melting point, for 2.5 min.(165) The unusual stability of the peroxide moiety in 195 has been attributed to the adjacent acetal functionality, which is believed to benefit from a stabilizing interaction between the antiperiplanar lone pair of the peroxide oxygen and the σ* orbital of the pseudo axial acetal C–O bond which has been attributed to hyperconjugation or an anomeric effect (Figure 14). According to natural bond orbital (NBO) calculations, this anomeric interaction is worth 17.0 kcal/mol, a strong stabilization due to the enhanced donor ability of the peroxide oxygen lone pairs that is based on the α-effect.(166)

Figure 14

Figure 14. Depiction of the anomeric effect in 195.

The cyclic peroxy ketal of 195 is an essential element of the pharmacophore in the expression of antimalarial activity. For example, the desoxy compounds 330 and 330a, which lack the peroxide bridge, are devoid of antimalarial activity, while replacing one of the peroxide oxygen atoms with methylene (331) also diminishes inhibitory activity; however, the 10-deoxo compound 332, which retains a peroxide group, is even more active than 195.(167) The expression of antimalarial activity by 195 depends upon activation of the peroxy moiety although the precise mechanism of bioactivation remains under debate. A carbon radical pathway which postulates that binding of the ferrous heme/nonheme exogenous Fe2+ to the peroxide bridge is followed by electron transfer to induce reductive scission of the peroxide bond, thereby producing oxygen-centered radicals 333 and 335, which rearrange to carbon-centered radicals 334 and 336 is one of the prevailing hypotheses (Scheme 16).(168a−c) The carbon-based radicals 334 and 336 are believed to react with parasite proteins that mediate critical biochemical pathways, thereby killing the organism.(168d)

Scheme 16

Scheme 16. Potential Modes of Action of 195 Relying upon Iron-Catalyzed Degradation to Oxygen- or Carbon-Based Radicals
The poor solubility of 195 in both water and lipid has provided an impetus to identify semisynthetic analogues with improved solubility and pharmaceutical properties.(103,105,169) Toward this end, the carbonyl group of 195 was reduced with NaBH4 to give 196, which was converted into a series of acetals that included the lipid-soluble artemether (202) and arteether (337) and the water-soluble artelinic acid (338) and 339 as well as artesunate (340), which also showed enhanced antimalarial activity.(169) Artemether (202), which can be taken orally, is the most prescribed analogue, while artesunate (340) is preferred for IV administration due to its high aqueous solubility. After oral administration, 202 and 340, but not 195, are rapidly biotransformed to DHA (196), the major active metabolite, primarily by CYP2B6 in the liver. Artemisinins kill malaria parasites within minutes, resulting in a rapid clinical response; however, they are limited by short half-lives. Therefore, artemisinin combination therapies are desirable for the first-line treatment of P. falciparum malaria as the artemisinin kills most parasites at the beginning of the therapy, while the other long-lasting drug eradicates the remaining parasites.(103)
The poor oral bioavailability associated with artemisinins has been ascribed to the hydrolytic instability of the acetal-lactone or acetal–acetal moieties. The stability of artemisinin analogues has been evaluated in simulated stomach acid (0.01 N HCl, pH 2.0 at 37 °C).(170) The disappearance half-lives ranged from 11 to 24 h, with the stability in the following order: 195 (24 h) > 196 (17 h) > 339 (13 h) > 338 (11 h). To improve the acid stability of artemisinin analogues, a series of nonacetal-based analogues containing a C–C bond at C10, as exemplified by 341-346, was prepared.(171) These compounds showed remarkable acid stability with disappearance t1/2 values ranging from 165 to 259 h in 0.01 N HCl, pH 2.0 and 37 °C. The non-acetal-based analogues 341343 possessed sufficient stability in simulated stomach acid to be suitable for oral administration, while 345 and 346 had sufficient stability and aqueous solubility to possess the shelf life required for an IV-administered formulation. The in vitro antimalarial activities of 341346 were either comparable to or superior to their acetal counterparts. Deoxoartelinic acid (346) also showed higher in vivo suppression toward Plasmodium chabaudi-infected mice than 202.(171)
Conversion of 195 to its 11-aza derivatives provides another approach to improve oral bioavailability.(164c,172) These azaartemisinins displayed a better antimalarial activity profile than that of 195. For example, oral administration of the amino- and hydroxy-functionalized 11-azaartemisinins 347 and 348 elicited robust antimalarial activity against multidrug-resistant Plasmodium yoelii in rodents. A series of 10-alkylaminoartemisinins that included artemisone (349) and artemiside (350) and exhibited improved aqueous solubility, enhanced metabolic stability, and higher oral activity, compared to artemisinins, have also been developed.(173) Notably, 349 was not susceptible to metabolic cleavage of the C–N bond to give 196, a compound believed to be a source of neurotoxicity associated with artimisnins in some patients.
Artimisinin derivatives remain the most potent and fast-acting antimalarial agents, but they are still limited by short half-lives in vivo, high cost of goods, and reliable supply issues. Every year, more than 100 tons of artimisinin are used to produce semisynthetic analogues, and the only practical way to access it is still through extraction from the plant. This has stimulated effort directed toward the development of fully synthetic, peroxide-containing drugs designed to present the pharmacophoric 1,2,4-trioxane moiety. Toward this end, the fully synthetic trioxanes 351 and 352 were prepared to allow comparison with their respective trioxolane counterparts, arterolane (353) and artefenomel (354).(174) The oral exposure of compound 351 was 4-fold higher than that of 353, but its overall antimalarial efficacy was not improved due to its lower intrinsic antimalarial potency. Trioxane 352 exhibited similar potency to 354, but its antimalarial efficacy was inferior due to its lower exposure following oral administration.(174)
Hybrid trioxaquines that combine a 1,2,4-trioxane with the 4-aminoquinoline moiety of antimalarial agent chloroquine (355) have been synthesized in an effort to develop molecules with a dual-mode of action that combines heme alkylation by the trioxane moiety with heme stacking by the aminoquinoline heterocycle to inhibit hemozoin formation.(175a,b) One of the early analogues, DU1302 (356), was potently efficacious following oral administration in a mouse model of malaria, but its structural complexity due to the presence of two chiral centers was a concern for further development.(175a) Subsequently, the simplified trioxaquine PA1103/SAR116242 (357), which is devoid of any chiral centers, was selected for development from a series of 120 active analogues. This compound was highly active in vitro toward several sensitive and resistant strains of Plasmodium falciparum and exhibited good oral bioavailability in rats. In mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia falciparum, low orally administered doses of 357 affected complete cures.(175b)
In addition to their antimalarial activity, artemisinin analogues have also been shown to have the potential for the treatment of cancer since the free radicals derived from the endoperoxide moiety following the encounter with iron can mediate cellular damage and initiate apoptosis in cells with high levels of iron.(175c) In general, artemisinin-derived dimers show higher antitumor activity than the more conventional monomeric artimisinin analogues.(175d) For example, dimer 358, IC50 = 43 nM, exhibited 8-fold enhanced potency in killing MTLn3 breast cancer cells in vitro compared to 196, IC50 = 360 nM, which translated into superior in vivo efficacy in suppressing the growth of MTLn3 tumors.(175d,e) The dimeric trioxane diphenylphosphate 359 was 88-fold more potent than 340 toward 23 human AML and acute lymphocytic leukemia (ALL) cell lines tested and interacted synergistically with sorafenib and venetoclax toward human acute leukemia cells in vitro and AML xenografts and primagrafts in vivo when tested in combination, collectively indicating the potential of the three drug combination as a therapy for AML and ALL.(175f) Mechanism of action studies in diffuse large B-cell lymphoma cells with the dimeric SM1044 (360) indicate that the antitumor effects involve the induction of autophagy and autophagy-dependent apoptosis.(175g) These dimers also offer advantages over monomers in terms of aqueous solubility and chemical stability.(175g)

Dispiro-1,2,4-trioxolanes

The development of a totally synthetic ozonide antimalarial with a quick onset of action, good oral bioavailability, and a single-dose regimen has been explored extensively.(164c,d,176) The first two dispiro-1,2,4-trioxolanes prepared and evaluated, 361 and 362, lacked antimalarial activity, suggesting that the peroxide bond was either too exposed or too sterically hindered to effectively interact with the heme iron(II). Trioxolanes 363 and 364, hybrids of 361 and 362 that take advantage of the low steric hindrance associated with one peroxide oxygen atom, which is thus more capable of accessing the iron(II) species, are active antimalarial agents. However, despite their potent in vitro and in vivo activity, both compounds possessed poor aqueous solubility (<1 μg/mL) and low oral bioavailability (<1% in rats), attributed to the high lipophilicity of the spiroadamantane trioxolane pharmacophore. Incorporation of an amine-containing acetamide side chain onto the cyclohexyl ring of 363/364, designed to reduce lipophilicity, afforded 353, which exhibited improved aqueous solubility and enhanced oral bioavailability in rats (F = 35%). In 2012, 353 was approved in India for the treatment for uncomplicated malaria infection as a fixed-dose combination with piperaquine administered in three doses on consecutive days.(176d)
Effort toward the development of second-generation ozonides has focused on improving the pharmacokinetic properties of 353 as a means of achieving a single-dose cure.(176c,d) Arterolane (353) has a relatively short half-life of 3 h in humans due to CYP3A4-mediated hydroxylation of the adamantane ring, which produces inactive metabolites, and decomposition catalyzed by Fe (II) in blood to give adamantane lactone and cyclohexanone as the cleavage products. Replacing the alkyl cyclohexyl moiety with an aryl cyclohexyl homologue ameliorated metabolic instability and also increased the stability in blood toward Fe (II) without compromising antimalarial efficacy. Final optimization of the aryl substituents afforded the highly potent and longer-acting 354, which offers the potential for a single-dose cure of uncomplicated malaria infection.(176d,e) This compound exhibited a half-life of greater than 20 h following oral dosing to rats, which compared to 1 h for 353 and 0.5 h for dihydroartimisinin (196), and an oral bioavailability of 76%, which compared to 35% for 353. In humans, 354 demonstrated an extended half-life of 46–60 h, which is essential for a single dose therapeutic schedule. Artefenomel (354) is currently in phase II clinical trials.(176d,e)

Dispiro-1,2,4,5-tetraoxanes

Compared to 1,2,4-trioxolane (365) and 1,2,4-trioxane (361), tetraoxane (366) is devoid of chiral centers and displays greater inherent thermodynamic stability, which has been rationalized in terms of a stereoelectronic “double anomeric effect” based on theoretical calculations (Figure 15).(166a) Tetraoxanes (367) also exhibit remarkable stability toward both strongly acidic (pH 1.6, MeOH/HCl, 37 °C) and basic (pH 12, NaOH/i-PrOH/H2O) conditions as well as harsh metal hydride reduction protocols, including exposure to LiAlH4.(177)

Figure 15

Figure 15. Depiction of the anomeric effects in 1,2,4-trioxolane 365, 1,2,4-troxane 361, and tetraoxane 366.

Potent antimalarial agents have been prepared based on the 1,2,4,5-tetraoxane scaffold 366.(178) While the unstable dispiro-1,2,4-trioxolane 365 lacked antimalarial activity in vitro, the tetraoxane homologue 366 is a potent antimalarial agent. As observed in the ozonide series, the fusion of the 1,2,4-trioxolane ring system to an adamantane core further enhanced chemical stability. Optimization of the side chain in the generic structure 367 in a fashion designed to counterbalance the lipophilicity of the adamantane moiety delivered RKA182 (368), formulated as the ditosylate salt, which demonstrated oral bioavailability in rats (38%) and mice (42%).(178b) Given its superior in vitro and in vivo activity compared to the artemisinins coupled with good oral bioavailability in rodent models, 368 was selected as a drug-development candidate.
However, 368 is associated with a relatively short 2.4 h half-life in rats following a single oral dose of 10 mpk, directing second-generation discovery toward overcoming the potential metabolic liability associated with amide-linked analogues.(178b) Following developments in the ozonide series, the amide side chain was replaced with a phenyl ring designed to improve metabolic stability, and a basic 4-fluoropiperidinylethyl moiety was incorporated as a phenyl substituent designed to reduce lipophilicity. This resulted in the identification of E209 (369) which exhibits good oral bioavailability across the species (62% in rats; 82% in mice; 40% in dogs). Allometric scaling using rat PK data predicted a terminal half-life of 24–30 h in humans (compared to half-lives of 1–2 h for currently available artemisinins) and an oral bioavailability of 62%, compatible with a single-dose cure, administered either as monotherapy or in combination.(178c,d)
The fully synthetic tetraoxanes 370 and 371 were also prepared for comparison with their respective trioxolane counterparts, 353 and 354.(174) Compound 370 showed comparable antimalarial oral efficacy to 353 despite similar in vitro activity and higher exposure in vivo. Compound 371 showed similar in vitro antimalarial activity to 354, but its oral activity was significantly reduced due to much lower exposure in vivo.

(N,O)-Aminals (R–N–C–O–R′)

In the absence of stabilizing group(s) designed to blunt amine basicity, simple (N,O)-aminals are generally less stable than their analogous acetals and ketals because protonation of the basic nitrogen atom is facile, which facilitates departure as a leaving group, resulting in significant sensitivity to hydrolytic degradation.(179a) However, there are circumstances where this kind of chemical reactivity can be beneficial, as exemplified by the antibiotic dirithromycin (372), which is a (9-N, 11-O)-aminal prodrug of 9(S)-erythromycyclamine (373) derived by conjugation with 2-(2-methoxyethoxy)acetaldehyde (374). The prodrug element is unstable under both acidic and neutral conditions and undergoes spontaneous, nonenzymatic degradation during absorption and in plasma to release the active macrolide antibiotic, thereby improving oral bioavailability (Scheme 17).(179) Following IV administration, conversion of 372 to 373 was complete within 1.5 h, with 60–90% conversion occurring during the first 35 min. In order to minimize acid-mediated degradation in the stomach, the prodrug 372 is formulated as enteric-coated tablets. Interestingly, despite being a prodrug, 372 is a more potent inhibitor of bacterial protein synthesis in vitro than 373, and the compound has been shown to bind to a complex of the 70S ribosome from Thermus thermophile and E. coli(180) In the X-ray cocrystal structure of 372 with the 70S ribosome from Thermus thermophile, one of the lone pairs of electrons on the oxygen atom of the prodrug moiety that is distal to the core of the molecule engages in a π-interaction with a His residue in the ribosomal protein uL4.(180)

Scheme 17

Scheme 17. Degradation of 372373 and Aldehyde 374
The degradation rate of (N,O)-aminals largely depends on the nature of the substituents on both C2 and the nitrogen atom. The stability of aminals derived from carbonyl compounds follows the order: formaldehyde > alkyl aldehyde > ketone, a trend that parallels the respective acetals and ketals and is related to the ability to stabilize the developing carboxonium (carbonylonium) intermediate (Scheme 18). For example, the 2,2-dimethyloxazolidine-based dipeptides 375 hydrolyzed rapidly in dilute trifluoroacetic acid (TFA) to give 377 or 378, while, in contrast, the unsubstituted oxazolidines 376 proved to be exceptionally stable, and much longer reaction times in the presence of stronger acids such as trifluoromethanesulfonic acid (TfOH) were required to induce ring opening to give 377 or 378 (Figure 16).(181a) Analogous to acetals and ketals, aminals with electron-withdrawing groups at C-2 can be resilient toward acidic hydrolysis, as exemplified by the CF3- and CF2H-substituted pseudoprolines 379 and 380, which remained intact upon exposure to TFA in CDCl3 or H2O for 4–72 h at room temperature.(181b,c) As might be anticipated, the N-acetyl group also contributes to the stability of these molecules since the free NH pseudoproline 381 epimerizes in the presence of BF3•OEt2 to give a mixture of 381 and 382 while its N-acylated homologue 383 is stable under these conditions with none of 384 detected. In addition to enhancing chemical stability, the CF3 and CF2H substituents increase the preference for a cis-amide bond orientation in 386 due to steric interference in the trans-topology 385, while the cis-topology of the CHF2-substituted pseudoproline 387 is further favored, attributed to the formation of a stabilizing H-bond between the CF2H hydrogen atom and the amide carbonyl.(181c) These hydrolytically stable pseudoproline derivatives may be useful in drug design but have yet to be gainfully exploited.(181d)

Scheme 18

Scheme 18. Mechanism of Acid-Catalyzed (N,O)-Aminal Hydrolysis

Figure 16

Figure 16. Structures and chemical stability under acidic conditions of pseudoproline derivatives.

A series of aminal-linked tetracyclic inhibitors of the HCV NS5A replication complex derived from the benzofuran prototype MK-4882 (388) has been developed in which a poorly basic indole nitrogen atom is part of the geminal diheteroatomic motif, as exemplified by 390 (Figure 17).(182) In order to improve the antiviral activities of 388 toward clinically relevant HCV GTs and resistance mutations, the benzofuran core was converted to an indole scaffold. This molecular edit allowed the introduction of a bridge between the indole nitrogen atom and C5 carbon of the proximal phenyl ring through either an ethylene (389) or an oxygen-containing linker (390) that enabled substitution in a region of the pharmacophore known to be tolerant. The tetracyclic indole derivatives 389 and 390 displayed comparable activity to 388 toward GT-1a and GT-1b HCV WT replicon systems although, interestingly, the ethylene analogue 389 showed reduced activity toward the GT-1a Y93H mutant (EC50 = 170 nM) that can arise as the result of selective resistance pressure from first-generation HCV NS5A inhibitors. However, the introduction of the oxygen atom in 390 improved the GT-1a Y93H inhibitory activity by 34-fold (GT-1a Y93H EC50 = 5 nM). While the aminal linkage in 390 was shown to be extremely stable toward hydrolytic cleavage, even under forcing conditions, the compound exhibited cytotoxicity in the low μM range (CC50 ≈ 1 μM). Fortunately, the toxicity could be circumvented by adding a phenyl substituent at the aminal carbon atom (C6), and one of the two resulting diastereomers, elbasvir (391, MK-8742), was on average an order of magnitude more potent than 388 toward most of the HCV NS5A mutations evaluated. Elbasvir (391) was metabolically stable in liver microsomal preparations obtained from rats, rabbits, dogs, and humans and in mouse, rat, dog, and human hepatocytes, but its oral bioavailability was still in the low to moderate range (9% in rats; 35% in dogs; 17% in monkeys), which can be attributed to its limited oral absorption, as suggested by its low passive permeability.(182e) Elbasvir (391) is marketed in combination with an HCV NS3/4A protease inhibitor under the trade name Zepatier as a once-daily oral treatment option for chronic HCV GT-1 and GT-4 infections.

Figure 17

Figure 17. Structures and evolution of HCV NS5A inhibitors.

Further study within this series was directed toward developing an inhibitor with potent activity against all genotypes and a minimal potency shift (∼10-fold) between the wild-type virus and clinically relevant polymorphisms. These efforts led to the discovery of ruzasvir (MK-8408, 392) as a potent, pan-genotype HCV NS5A inhibitor with optimized activity toward common resistance-associated polymorphisms.(182c,d) The fluorine substituent in 392 contributed to a significant improvement in GT-1a Y93H potency. Similar to 391, 392 showed low to moderate oral bioavailability in rats (5%) and monkeys (10%); however, combination trials with 392 were discontinued after phase II clinical trials for business reasons.
Clavulanic acid (393) is a naturally occurring β-lactam derivative in which an acylated hemiaminal is embedded at the fused ring junction, a strained structural element that is integral to its biological activity.(183) Clavulanic acid (393) has little intrinsic antibacterial activity but is a mechanism-based inhibitor of serine-based β-lactamases; consequently, it is typically combined with penicillin-type antibiotics to overcome resistance by preventing β-lactamase-mediated degradation of the antibiotic, thus enhancing their effectiveness toward bacteria that express these enzymes.(183) The proposed mode of β-lactamase inhibition by clavulanic acid is presented in Scheme 19 and, while complex, relies upon the intrinsic reactivity of the embedded N–C–O moiety that is unmasked by the enzyme after deacylation of the oxazolidine nitrogen atom. Cleavage of the β-lactam ring of 393 as the result of an attack by the catalytic serine-70 (Ser70) of the β-lactamase relieves the stabilizing constraint on the N–C–O element, releasing the oxazolidine ring to give 394, which readily opens to generate an imine intermediate 395 that is poised to engage in several pathways of reactivity.(184) Tautomerism to the enamino ester 398 would reduce the susceptibility of the ester moiety toward hydrolysis while decarboxylation of imine 395 to give 399 followed by tautomerism to the enamino ester 400 has also been observed. Fragmentation of the imine 395 by hydrolysis releases (R)-2-amino-5-hydroxy-3-oxopentanoic acid (397), leaving an enzyme acylated by 3-oxopropanoic acid (396). Trapping of the imine 395 by Ser130 of the enzyme to generate a cross-linked, irreversibly inhibited enzyme has also been proposed with the elimination of 397 to give an alkoxyacrylate 402 via 401.(184) Clavulanic acid (393) is maximally stable at pH values between 5.8 and 6.5, with degradation in alkaline solutions proceeding approximately 8-fold faster than in acidic media, while comparison with penicillin G indicates a 10-fold faster degradation at neutral pH and a 5-fold faster rate at high pH while acid stability is comparable.(185) The acid- and base-promoted decomposition of clavulanic acid presumably involves β-lactam ring cleavage and/or opening of the oxapenam ring.(185) Clavulanic acid exhibits high oral bioavailability (70–97%) when administered alone with 20 to 60% of the drug excreted in the urine unchanged, but varied from 31% to 98% when coadministered with amoxicillin, suggestive of a DDI.(186)

Scheme 19

Scheme 19. Proposed Mechanism of Inactivation of Serine-Containing β-Lactamase Enzymes by 393
Rezafungin (CD101, 404) is an interesting antifungal agent derived from anidulafungin (403) in which the acylated and alkylated hemiaminal is further stabilized by the pendent positively charged choline ether moiety (Figure 18).(187) This macrocyclic peptide is a semisynthetic derivative of the echinocandin class that inhibits fungal cell wall synthesis, a mechanistic phenotype that has led to them being referred to as the “penicillins of antifungals”.(188) However, the chemical instability and poor solubility associated with echinocandins impose serious limitations for manufacturing, storage, and the development of suitable dosage forms. Chemical decomposition is initiated by the facile cleavage of the acylated hemiaminal in 403, which occurs in both plasma and buffered solutions. In contrast, 404 showed no appreciable degradation in PBS buffer and was quite stable in plasma from rats, dogs, monkeys, and humans with 9%, 21%, 6%, and 7% degradation occurring over 44 h, respectively. The ring-opening step that initiates the chemical degradation results in a carboxonium (carbonylonium) intermediate that, in the case of 404, is disfavored due to the presence of the proximal quaternary ammonium substituent, reflecting the generation of a repulsive and destabilizing interaction between the dual positive charges (Figure 18). The absence of a significant amount of both the acyclic aldehyde intermediate and GSH adducts also suggested the potential for reduced toxicity.(187b) The positively charged choline ether also greatly enhanced aqueous solubility. Given its exceptional stability and good solubility, 404 is undergoing phase III clinical evaluation as a once-weekly IV formulation for the prevention and treatment of invasive fungal infections.(187,188)

Figure 18

Figure 18. Structures and degradation pathways of 403 and 404.

An acylated cyclic hemiaminal ether moiety is a prominent structural feature of the HIV-1 integrase inhibitor dolutegravir (407) (Figure 19).(189) A hydroxyl substituent was introduced to the saturated piperazinone ring of the lead compound 405 to improve potency toward a key clinically relevant integrase mutant, but the hemiaminal functionality posed concerns for chemical stability. This was addressed effectively by annealing it with the adjacent methyl group to form a tricyclic analogue which produced two enantiomers 406a and 406b that were resolved and evaluated in pure form with no interconversion or chemical stability issues observed. Both enantiomers wereequipotent and displayed good oral bioavailability; however, an enantioselective synthesis was not readily available, and resolution of the racemate was not an option for production in terms of cost of goods. Fortunately, when the enantiomerically pure α-methylamino alcohol 409 was used in the formation of these cyclic aminals from 408, a 20:1 diastereoselectivity was observed, and 410 was isolated in 81% yield after single recrystallization (Figure 19). Hydrogenation gave 407, which was comparable to the unsubstituted enantiomers 406a and 406b. In this case, the synthesis methodology played an important role in selecting candidates for further development, and 407 was approved for the treatment of HIV-1/AIDS in the United States in 2013 and is on the WHO’s List of Essential Medicines.

Figure 19

Figure 19. Principle behind the design and synthesis of the HIV-1 integrase inhibitor 407.

The HIV-1 integrase inhibitor bictegravir (411) retains elements of the metal-binding pharmacophore of 407 but combines a bridging element installed across the cyclic aminal ring to afford a bicyclic system with an inverted configuration at the hemiaminal ether carbon atom.(190) Bictegravir (411) retains the antiviral properties of the progenitor drug but demonstrates reduced PXR activation and a longer t1/2 in humans (19 h compared to 14 h), as summarized in Table 8. The additional fluorine substituent on the benzylamine contributed to enhanced solubility, and 411 was approved as part of combination therapy in 2018.(191)
Table 8. In Vitro Profiling Data for 407 and 411
drugEC50 (nM)G140S/Q148R (fold shift)Fu in human plasmaPXR (% Emax at 15 μMsolubility (mg/mL)F rat, dog (%)t1/2 (h, human)
4071.74.80.70515352, 1714
4111.92.00.301811950, 2819
A series of bicyclic hemiaminal ether-based BACE1 inhibitors, of which 413 is a representative, were designed after the furo[3,4-d][1,3]thiazin-2-amine picolinamide LY2886721 (412), a potent BACE1 inhibitor that advanced to phase II clinical trials where it was examined as a potential therapeutic for the treatment of early Alzheimer’s disease.(192) Modeling of 412 bound to the BACE1 active site indicated no specific interaction between the furan oxygen and the protein, suggesting that relocation of this oxygen atom to the adjacent position to create a hemiaminal ether linkage would not compromise an important drug–target interaction. Indeed, the hemiaminal ether 413 exhibited comparable BACE1 inhibitory activity to 412, indicating that the effects of the altered relationship between the ring oxygen atom and the isothiourea moiety that intimately engages the BACE1 enzyme were not detrimental. While the original furo[3,4-d][1,3]thiazin-2-amine core in 412 required a complex, multistep synthesis, the bicyclic aminal intermediate was readily prepared through a one-pot, three-step operation beginning with 414 to produce 418 through the intermediacy of 415, 416, and 417, as depicted in Scheme 20. These bicyclic hemiaminal ethers proved to be very stable under acidic conditions, with no appreciable decomposition observed when incubated at pH values ranging from 1 to 10 at 40 °C for 24 h.(192)

Scheme 20

Scheme 20. Design of 413 and the Synthetic Approach Developed to Access the Core Molecule 418
ORN0829 (421), an orexin antagonist recently identified as a clinical candidate for the treatment of insomnia, is built on a cyclic hemiaminal scaffold that has been shown to possess good chemical stability.(193) The design concept is depicted in Figure 20 and sought to introduce conformational constraint into the amide moiety of 419 by installing the piperidine heterocycle in 420, a modification that fully preserved the binding profile of the progenitor. However, replacing the piperidine ring in 420 with the cyclic aminal in 421 was sufficient to lower lipophilicity to the preferred range for CNS drugs without materially affecting antagonist potency. The two isomers 422 and 423 were 3-fold less potent than 421, while the enantiomer (+)-424 and ring contracted oxazolidine 425 were both much weaker antagonists. All of these analogues demonstrated similar metabolic stability in HLMs, while evaluation of 421 at pH 1.2 and 37 °C for 24 h confirmed chemical stability under acidic conditions. ORN0829 (421) exhibited appropriate pharmacokinetic properties, with an especially rapid tmax and a short t1/2 designed to avoid a hangover of daytime drowsiness the morning following ingestion. The oral bioavailability of 421 was 5.5% in the rat and 61.6% in the dog, with a peak brain concentration in rats of 2.33 nM following a 3 mpk dose, reflecting a brain to plasma ratio of 1:7.(193)

Figure 20

Figure 20. Design principle behind the discovery of 421.

An interesting and unique hemiaminal motif is found in the cephamycins, a group of β-lactam antibiotics and are structurally related to the cephalosporins.(194a) The cephamycins possess an α-disposed methoxy substituent at the C7 position (426, Figure 21), which confers unusually high resistance to degradation by β-lactamases, presumably a reflection of steric hindrance of the adjacent carbonyl moiety of the β-lactam ring.(194b) In these molecules, aminal hydrolysis would be expected to proceed via a carboxonium (carbonylonium) ion intermediate 427 that is disfavored due to the presence of the adjacent carbonyl moiety and the additional ring strain that would be introduced by planarization (Figure 21). Cephamycin C (428) displayed a half-life of 459 h at pH 6.0 and was very stable at pH values ranging from 3.0 to 7.5, with higher degradation rates at pH values beyond this range.(195) However, despite its high resistance toward degradation by several β-lactamases, 428 was active only against Gram-negative bacteria, and modification of the C7 amide element was required to afford cefoxitin (429), which exhibits a broader spectrum of activity that extends to include Gram-positive bacteria.(194) Cefoxitin (429) is administered by injection into a muscle or vein for the treatment of many kinds of bacterial infections, including severe or life-threatening forms.(194b) Other cephamycin derivatives include cefotetan (430), which incorporates an unusual C-7 thioacetal-containing amide moiety, and cefmetazole (431), both of which are semisynthetic, while moxalactam (432) is completely synthetic. All of these antibacterial agents contain a 1-methyl-1H-tetrazol-5-yl)thio)methyl C-3 side chain moiety that is susceptible to metabolism to release N-methylthiotetrazole (433, NMTT), which has been associated with hypoprothrombinemia. For this reason, 431 and 432 have been discontinued in the United States, although 430 remains on the market.

Figure 21

Figure 21. Structure of the carboxonium (carbonylonium) ion intermediate that would be formed if 426 hydrolyzed by loss of the amine substituent.

The development of the orally bioavailable, mechanism-based, polymorphonuclear leukocyte (PMN) elastase (PMNE) inhibitor L-694,458 (438, DMP-777) originated with the relatively simple azetidinone (±)-434.(196a) However, 434 was rapidly hydrolyzed even under mild conditions with a disappearance t1/2 of 2 h at pH = 8.0 and 25 °C while virtually instantaneous decomposition was observed in human blood at 25 °C, reflecting the inherent reactivity of the multiple electrophilic centers. The O-acetyl group, which was considered to be unstable toward nucleophiles and/or esterases, was replaced with a 4-carboxylic acid-substituted phenol, with the resulting 435 possessing improved hydrolytic stability (disappearance t1/2 = 9 h at pH = 8.0 and 25 °C) and improved aqueous solubility while retaining potent mechanism-based, enzyme inhibitory activity. However, since 435 was still susceptible to both N-deacylation and β-lactam ring opening, the N-benzylcarbamoyl analogue 436 was prepared in an attempt to slow the N-deacylation process. This molecule offered higher chemical stability with a t1/2 of >80 h, presumably because the carbamoyl moiety is intrinsically less electron-withdrawing than an acyl group. The stability of the β-lactam nucleus in 436 was further enhanced by introducing a second alkyl group at C3, which projects into the S1 subsite of the enzyme. The additional substituent sterically interferes with nucleophiles approaching the β-lactam carbonyl, with 3,3-diethyl substitution providing the optimal balance of stability, inhibitory potency, and in vivo efficacy.(196b) Incorporation of a (R)-n-propyl substituent at the benzylic methylene resulted in a further 100-fold improvement in inhibitory potency compared to the unsubstituted precursor. Further modifications to both phenyl rings led to the identification of L-680,833 (437) as a potent, orally active PMNE inhibitor.(196c) L-680,833 (437) was completely orally bioavailable in rats although less so in monkeys (F = 23%), and the terminal elimination t1/2 values were 2.3 and 5.8 h in rats and rhesus monkeys, respectively, following a single IV dose. These data also confirmed the improvement in intrinsic chemical and metabolic stability. L-680,833 (437) was selected as a development candidate but was subsequently replaced with L-694,458 (438), which was advanced into phase I clinical trials in adult patients with cystic fibrosis.(196d) L-694,458 (438) had higher oral bioavailability than 437 in rhesus monkeys (39% compared to 23%) but lower in rats (65% compared to 100%). A 40 mpk oral dose administered to rhesus monkeys resulted in a protracted plasma concentration–time profile characterized by a delayed tmax (8–24 h) and a long terminal t1/2 of 6 h. The major metabolite in human and rhesus monkey liver microsomes was the catechol resulting from cleavage of the methylenedioxy moiety. In RLM, the primary metabolic pathway was oxidation of the basic amine to give the N-oxide of the methyl-substituted piperazine nitrogen atom. Therefore, the embedded aminal functionality in these inhibitors appeared to be both chemically and metabolically stable. The chemical stability can be attributed to the reduced availability of the electrons on the nitrogen atom to promote expulsion of the substituted phenol moiety and the strain that would be introduced into the four-membered ring by iminium formation (Scheme 21).

Scheme 21

Scheme 21. Degradation Pathway for 438 Involving the Departure of the Phenol Moiety, A Process That Is Disfavored Electronically and by the Introduction of Strain in the Azetidinone Ring
The widely prescribed sleeping medication eszopiclone (441) features an embedded O-acylated (N,O)-hemiaminal, which is sufficiently stable both chemically and metabolically to be 80% oral bioavailable in humans.(197) Eszopiclone (441) is rapidly absorbed after oral administration, with a tmax ranging from 1 to 1.3 h, thus leading to a quick onset of action. The two major metabolites identified result from N-demethylation of the tertiary amine to give 442 and oxidation of the basic piperazine nitrogen atom to the N-oxide 443 in the liver.

Nucleoside Analogues

The (N,O)-hemiaminal moiety is a structural motif found in the majority of ribose-based nucleoside and nucleotide analogues that are used to treat a range of viral infections and cancers.(198) The (N,O)-hemiaminal linkage in nucleosides is hydrolytically labile under acidic conditions and has presented problems in the development of some ribose-based nucleoside analogues.(199,200) Hydrolytic reactivity is sensitive to the structure of both the ribose and the base, with 2′,3′-dideoxy nucleosides more labile than 2′-deoxyribonucleoside analogues, which, in turn, are more labile than ribonucleosides, as captured by the data compiled in Table 9 for a series of adenine nucleosides 444450.(199) The higher stability of ribonucleosides has been attributed to the presence of the electronegative 2′-oxygen atom, which destabilizes the oxacarbonium ion intermediate (Scheme 22).(199) Moreover, purine derivatives are considerably more reactive than pyrimidine-based derivatives, and the stability of both is influenced by structural modifications to the heterocycle.(199) The reaction is believed to occur via an acid-catalyzed dissociation of the base after protonation, with glycosyl bond rupture the rate-determining step reflecting an A1-type of mechanism (Scheme 22).(199b,c,e) Despite these concerns, many nucleoside and nucleotide analogues incorporating modified ribose moieties have been successfully developed into important, orally administered drugs.(198)

Scheme 22

Scheme 22. A1 Mechanism of Acid-Catalyzed Hydrolysis of Nucleosides
Table 9. Rate Constants for the Acid-Catalyzed Hydrolysis of a Series of Adenine Nucleosides 444450(199d)
The 2′,3′-dideoxynucleosides dideoxycytidine (ddc, zalcitabine, 451) and dideoxyinosine (ddI, didanosine, 452) are early examples of nucleoside-based inhibitors of HIV-1 reverse transcriptase developed to treat HIV-1 infection.(198) Due to the absence of hydroxyl substituents at the 2′- and 3′-positions of the ribose ring, both compounds are sensitive to glycoside cleavage under acidic conditions. For example, ddA (447) undergoes acid-catalyzed degradation with a rate constant that is 42,000 times faster than adenosine (444), which can be attributed to the removal of the inductive electron-withdrawing effect of the 2,3-hydroxyl substituents which would destabilize the oxocarbonium intermediate.(199d) Degradation of ddA (447) upon exposure to gastric acid following oral administration gave adenine (453), which is further metabolized to give 2,8-dihydroxyadenine (454), which concentrates in renal tubules where it crystallizes causing nephrotoxicity.(201) ddA (447) also undergoes cellular deamination to ddI (452) which is converted via 456 to ddA-5′-triphosphate (457), the active metabolite responsible for inhibiting HIV-1 reverse transcriptase (Scheme 23).(202) Therefore, ddA (447) can be considered as a prodrug of ddI (452), but the latter offers the advantage of eliminating the release of adenine upon acid-mediated degradation and thus avoiding the potential for nephrotoxicity. However, ddI (452) is still susceptible to acid hydrolysis upon oral administration while its limited solubility at low pH values presents a problem for formulation. An early oral formulation involved large buffered tablets containing calcium carbonate and magnesium hydroxide buffers designed to help neutralize the stomach acid and possibly improve its solubility, but the resulting large and bitter-tasting pills were not only difficult to take but also caused diarrhea and other GI side effects.(203) Ultimately, an enteric coated form using small capsules was developed to protect ddI (452) from hydrolysis in the acidic milieu of the stomach and facilitate absorption from the intestine. The enteric coated form delivered higher oral bioavailability than the buffered tablet (36% compared to 25%), but lower than the oral solution (or reconstituted powder) administered with an antacid (F = 41%).(203) ddI (452) became the second drug marketed to treat HIV-1 infection in the United States when it was approved by the FDA in 1991.(198)

Scheme 23

Scheme 23. Degradation and Metabolism of 447
In contrast to ddA (447), dideoxycytidine (ddC, zalcitabine, 458) showed good stability in acid and was not subject to appreciable metabolic deamination to give dideoxyuridine (459) in either mice or humans although this pathway was measurable in monkeys.(204a) The primary metabolic pathway in the intracellular environment involved sequential phosphorylation to the monophosphate 460, the diphosphate 461 and finally dideoxycitidine-5′-triphosphate (ddC-TP, 462), the active metabolite (Scheme 24). ddC (458) exhibited an oral bioavailability of 80% in humans, which confirmed its stability in the gut, and became the third drug approved to treat HIV-1 infection in the US in 1992.(204b) However, 458 was discontinued in 2006 because of an inconvenient thrice daily dosing frequency as well as its association with serious side effects such as painful peripheral neuropathy.

Scheme 24

Scheme 24. Intracellular Metabolism of 458
An electronegative fluorine was introduced at C-2′ of the ribose of ddA (447) and ddI (452) as a strategy to destabilize the oxocarbonium ion intermediate in the hydrolytic mechanism, thus decreasing the rate of hydrolysis (Scheme 25).(205−207) Indeed, 463, 2′-F-dd-ara-A (464), and 2′-F dd-ara-I (465) were found to be completely resistant to acid hydrolysis at pH 1 and 37 °C while the respective parent compounds had a t1/2 values of less than 1 min.(205a) The acid stability of 2′-F-dd-ara-A (464) was reflected in its increased oral bioavailability relative to ddA in beagle dogs.(205c) The fluoro analogues 464 and 465 appeared to be comparably potent to the parent compounds toward HIV-1 but were also more cytotoxic while 463 was inactive in a cell culture.(205a)

Scheme 25

Scheme 25. Hydrolysis of 2′-F-ara-ddI and 2′-F-ara-ddA Disfavored by the Presence of the 2′-F Atom, Which Destabilizes the Oxocarbenium Ion Intermediate
Fludarabine (466) and cladribine (467) are first-generation purine nucleoside analogues that were advanced through clinical trials and approved for the treatment of leukemias (Scheme 26).(208−210) The 5′-monophosphate moiety in 466 acts as a prodrug to facilitate formulation since embedded nucleoside is very poorly soluble.(209) One drawback with 466 is the phosphorolytic breakdown of the N-glycosidic bond by the bacterial enzyme purine nucleoside phosphorylase expressed in Escherichia coli found in the GI tract which releases 2-fluoroadenine (469). This presents problems because 469 is metabolized in vivo to 2-fluoro-adenosine triphosphate (470), a toxic metabolite with no anticancer activity (Scheme 26).(209) Cladribine (467) is also a substrate for rapid metabolism by bacterial nucleoside phosphorylases to release 2-chloroadenine (471), which is much less toxic than 2-fluoroadenine (469).(210a,b) Cladribine (467) is also sensitive to hydrolytic degradation at the acidic pH of the GI tract.(210,211a−d) Collectively, these data led to the design of clofarabine (468), a derivative of 467 in which a fluorine atom is installed at the C-2′ position in an attempt to reduce both acid- and enzyme-catalyzed ribose cleavage, thus leading to improved oral bioavailability.(211a−d) Clofarabine (468) was comparable to 467 in potency but more cytotoxic than fludarabine 466 to three human cell lines and one murine leukemia (L1210) cell line.(211a−c) Unlike cladribine (467), clofarabine 468 was stable at pH 2 and significantly more resistant to cleavage by E. coli nucleoside phosphorylase, with the degradation rate approximately one-third that of cladribine 467 and fludarabine 466.(210,211a−d) The combination of both effects translated into enhanced oral bioavailability for 468 (57% compared to 40% for cladribine 467) which was approved for the treatment of pediatric leukemia by the FDA in 2004.(211e,f)

Scheme 26

Scheme 26. Metabolism of 466 and 467
Cytarabine (ara-C, 473), a chemotherapy drug whose synthesis was inspired by the two marine natural products spongothymidine (472a) and spongouridine (472b) which were isolated in the early 1950s, is the backbone of intensive acute myeloid leukemia (AML) therapy.(212,213) Due to its poor permeability across intestinal membranes, ribosidic bond cleavage and deamination by cytidine deaminase in both the gut and liver to produce the biologically inactive uracil arabinoside (ara-U, 475), which is excreted by the kidneys, 473 exhibited poor oral bioavailability (ca. 20%) and a short plasma half-life.(212b) This PK profile necessitates continuous infusion of 473 in order to maintain adequate plasma drug levels, with the dose adjusted based on patient liver and kidney function.(214) More recently, BST-236 (aspacytarabine, 474), a prodrug in which the primary amine of 473 is acylated with asparagine, has been developed to deliver high cellular drug levels while reducing plasma exposure as an approach to mitigating systemic toxicity.(215) Prodrug 474, which is inactive and nontoxic and resists deamination in the systemic circulation by virtue of derivatization of the metabolically vulnerable amine, enters leukemic cells intact where it gradually releases 473 via nonenzymatic hydrolysis, resulting in cell death. Aspacytarabine (474) is currently in phase 2b clinical trials for the treatment of aged adult patients (75 years or older) with AML.
An early effort to investigate the impact of fluorine substitution on the ribose ring led to the synthesis of 2′-F-arabinonucleoside (F-ara-C, 476), which demonstrated comparable inhibitory activity toward L1210 leukemia cells as 473 (Figure 22)(216) However, the deamination rate for 476 was similar to 473 resulting in less than robust antitumor activity in mice.(198,217) Structural evolution by further modification at the C-2′ position with geminal difluoro substitution afforded gemcitabine (dFdC, 477), an effective antitumor agent marketed as Gemzar.(218) The two fluorine atoms in 477 influence the conformation of the ribose ring in a unique fashion in which the 2′-carbon atom is deformed out of the plane of the furan ring, a shape distinct from the more conventional north or south nucleoside conformation that may contribute to its enhanced biological activity.(198b) Gemcitabine (477) is administered via intravenous infusion due to its poor intestinal permeability and significant deamination to its inactive uridine metabolite 2,2-difluorodeoxyuridine (dFdU, 478) by deoxycytidine deaminase in both human plasma and liver, both of which contribute to the low, 10%, oral bioavailability (Figure 22). These problems have been circumvented by the development of an orally active prodrug, LY2334737 (479) in which the exocyclic amine is acylated with the lipophilic valproic acid, blocking the site of deamination while enhancing membrane permeability.(219) Prodrug 479 showed good chemical stability (approximately 21% decomposition at pH 1 but completely stable after 4 h at 40 °C, pH 6–8) and was resistant toward enzymatic degradation, with no appreciable hydrolysis observed in small intestine homogenates.(219) In addition, the in vitro hydrolysis rate in human liver incubations was relatively low. These data suggested that the prodrug would transit the GI tract as the intact prodrug due to its chemical and enzymatic stability while low levels of activation in the liver by carboxylesterase-2 would provide for a sustained delivery of 477 to the systemic circulation.(219b) Indeed, 479 demonstrated oral efficacy in human colon cancer xenografts in mice and the molecule was advanced into phase I clinical trials.

Figure 22

Figure 22. Evolutionary path from 472477.

Sofosbuvir (480) is a notable and prominent example among 2′-fluorinated antiviral nucleoside and nucleotide analogues (Scheme 27).(220) The phosphate prodrug moiety of 480 is unmasked in the liver to give the monophosphate 481 which is converted to its active triphosphate 482, a potent inhibitor of HCV NS5B polymerase (Ki = 0.42 μM) with a long intracellular t1/2 of 38 h. PSI-6206 (483), the nucleoside derived from 481, was inactive in the HCV replicon assays due to its poor enzymatic phosphorylation.(220) Sofosbuvir (480) displayed significant potency in the HCV subgenomic replicon assay, produced high levels of triphosphate 482 in primary hepatocytes and in the livers of rats, dogs, and monkeys following oral administration. Sofosbuvir (480) demonstrated robust antiviral efficacy in the clinic and is a component of several combination therapies that produce cure rates of >95% in all patient populations. In 2015, 480 was designated as an essential medicine by the WHO.

Scheme 27

Scheme 27. Structure of 480 and Its Intracellular Metabolic Pathway to the Active Triphosphate 482
As observed with 2′,3′-dideoxynucleosides, the chemical stability of 2′,3′-dideoxy-2′,3′-didehydronucleosides also depends on the identity of the base moiety.(221) Both stavudine (d4T, 484) and d4U (485) exhibit good stability under acidic conditions (t1/2 = 26 and 15 h, respectively, at pH 1) despite the potential to form the presumed stabilized 2,5-dihydrofuran-2-ylium intermediate 489 by an A1 mechanism which affords the furan 490 (Scheme 28), while d4C (486) degraded relatively quickly when exposed to low pH conditions (t1/2 = 0.2 h at pH = 1), presumably a function of the facility for protonation of the base.(221) The poor oral bioavailability of d4G (487) has been attributed to its highly labile nature under acidic conditions since this nucleoside degrades with a t1/2 of <2 min at pH = 2.(221b,222) Stavudine (484) is one of the most orally bioavailable nucleoside analogues (F ∼ 100% in humans) and although its elimination t1/2 in humans is relatively short (1.6 ± 0.23 h), the active triphosphate metabolite exhibits an intracellular t1/2 estimated to be 7 h, supporting BID dosing of the drug.(223) Stavudine (484) was approved for use by the FDA in 1994 but it has been gradually phased out since 2010 due to its association with metabolic toxicity and long-term complications such as lipoatrophy, peripheral neuropathy, and lactic acidosis.

Scheme 28

Scheme 28. Proposed Decomposition Pathway for 2′,3′-Dideoxy, 2′3′-Didehydro Nucleoside Analogues
Acyclic nucleoside analogues incorporating hemiaminal motifs can also possess adequate stability for oral delivery as demonstrated by acyclovir (492) and ganciclovir (493) which are guanosine mimics licensed to treat herpes simplex virus (HSV) and human cytomegalovirus (HCMV) infections, respectively.(198,224) Both compounds exhibit low oral bioavailability attributed to poor membrane permeability and modest aqueous solubility rather than hydrolytic instability of the acyclic, formaldehyde-based aminal functionality. However, derivation of the primary hydroxyl moiety as the l-valine ester increased the oral bioavailability in humans from 15% to 54% for acyclovir in the context of 494 and from 9% to 65% for val-ganciclovir (495).(225) While introduction of the prodrug moieties resulted in enhanced solubility, the major factor subtending the improved oral bioavailability is their recognition by the PEPT1 transporter which facilitates absorption from the lumen of the small intestine, with the active drugs released by esterases in mucosal tissue.(226)

(O,S)-Acetals (R–O–C–S–R′)

(O,S)-Acetals are considerably more stable than (O,O)-acetals because sulfur has a much reduced tendency toward protonation than oxygen due to its lower electronegativity (2.58 for S compared to 3.44 for O) which translates into low basicity.(227) Consequently, expulsion of the sulfur to generate a carboxonium (carbonylonium) intermediate is not favored (Scheme 29). If the oxygen atom protonates, the resulting carbenium/sulfonium species is expected to be poorly stabilized since, as a third period element, the lone pairs of electrons on sulfur reside in 3p orbitals which do not overlap well with the 2p orbitals on carbon (Scheme 29).(228) This effect may be exacerbated by the longer C–S bond compared to a C–O bond and the overall circumstance is that the carbenium/sulfonium intermediate (Scheme 29) is not readily stabilized by sulfur. Consistent with the hydrolysis rate being dependent on the stability of the carbenium intermediate, 2-(4-methoxyphenyl)-1,3-dioxolane hydrolyzes 1330-fold faster in water at 30 °C than the corresponding 1,3-oxathiolane.(227b) However, similar to (O,O)-acetals, the stability (O,S)-acetals also shows dependence on the nature of the C2 substituent, as shown by the rate constants for hydrolysis of compounds 496ae in aqueous dioxane in the presence of 1 M HCl at 30 °C compiled in Scheme 29. The electron donating OMe reduces hydrolytic stability by 40-fold while an electron-withdrawing NO2 increases hydrolytic stability by 40-fold.(227b)

Scheme 29

Scheme 29. Acid-Catalyzed Decomposition Pathway for (O,S)-Acetals and Kinetic Data for Hydrolytic Degradation
The 3′-thionucleoside 497 (3TC, lamivudine) was discovered in 1998 and evaluated initially as the racemate BCH-189, a mixtue that demonstrated potent antiviral activity in cell culture.(229) The design rationale to replace the 3′ carbon atom of the ribose ring in ddC (458) with a sulfur atom was based on the anticipation that the shape mimicry of the ribose ring as well as the electronic environment in the 3′ region would play an important role in the activity and selectivity of the nucleoside analogues.(229) Both the unnatural l-isomer 497 and the natural d-enantiomer 498 exhibited similar potency, which, at the time, was very surprising since all previously known active nucleoside analogues possessed the natural d-sugar configuration. Interestingly, 498 inhibited host cell DNA polymerase, a source of toxicity with nucleoside analogues, while unnatural l-enantiomer 497 was devoid of this activity. Lamivudine (497) possessed favorable pharmacokinetic properties (F = 86%; t1/2 = 13–19 h in humans), which confirmed the stability of the (O,S)-acetal functionality in the acidic milieu of the stomach, and was approved by the FDA in 1995 and it is included in the WHO’s List of Essential Medicines.
Soon after the disclosure of 497 in 1989, a series of 5-substituted analogues was explored from which the 5-fluoro analogue emtricitabine (FTC, 499) offered a similar antiviral and toxicity profile to the prototype.(230) In this series, the unnatural l-(−)-enantiomer (499) was approximately 100-fold more potent than the natural d-(+) isomer 500. Also, in contrast to 497 and 498, neither 499 nor 500 showed any cellular toxicity. The antiviral potency and tolerability of 499 are comparable to 497, and the drug was approved for use in the US in 2003. Currently, over 90% of the HIV-1-infected patients in the US are prescribed with either 497 or 499 and, from this perspective, the replacement of the 3′-carbon of the ribose ring with a sulfur atom to form an (O,S)-acetal has had a profound and long-lasting impact on HIV-1 therapy.
The value of the sulfur atom in the context of 497 and 499 is further underscored by the dioxolane homologue troxacitabine (L-OddC, 501) and its 5-fluoro analogue 502, both of which exhibit potent antiviral activity toward HIV-1 and HBV but also demonstrated significant cellular toxicity due to inhibition of host DNA polymerases.(231) The oral absorption of 501 in rats was slow, resulting in highly varied bioavailability between individual rats that amount to 41 ± 27% based on urinary excretion data and 37 ± 25% based on plasma exposure data; therefore, 501 was administered via an IV infusion in clinical studies.(232c,d) The (O,S)-acetal 497 offers improved pharmacokinetic properties compared to the acetal 501 with an oral bioavailability of 86% in humans. Due to its selective toxicity toward several solid tumor cell lines, including hepatocellular and prostate cell lines as well as its activity against solid tumor growth in several human xenograft models, 501 was advanced into phase III clinical trials for cancer treatment using an IV infusion. However, further development of 501 was discontinued for business reasons.(231a,232,233)
l-(+)-1-[4-(Hydroxymethyl)-1,3-dioxolan-2-yl]-5-fluorouracil (504) represents a rare example of a triheteroatomic motif in which three heteroatoms are bound to a single sp3 carbon atom.(234) While the compound was fully characterized, it decomposed upon purification by silica gel chromatography (Scheme 30). The stability of the carboxonium (carbonylonium) ion 506 presumably contributed to the facile cleavage of the glycosyl bond to release the base 505. A subsequent, regioselective SN2 substitution gives the formate 507, which hydrolyzes to the diol 508 (Scheme 30). The chemical instability associated with 504 suggests that simple unstabilized triheteroatomic motifs may be poor vehicles for oral drug design.

Scheme 30

Scheme 30. Decomposition of 504 and Reassembly to Give 507 and Diol 508
An (O,S)-acetal moiety is a feature of the dual SGLT inhibitor sotagliflozin (292), developed for its potential to treat both type I and II diabetes mellitus.(235a) This compound displays good oral bioavailability and a long half-life in humans. Interestingly, the corresponding methoxyglycoside 509 is a selective SGLT2 inhibitor; so, in this context, simply switching from a methoxy to a thiomethyl substituent transforms a selective SGLT2 inhibitor into a dual inhibitor. LX2761 (510) is another thiomethyl-containing dual SGLT inhibitor that exhibits balanced potency but acts locally in the GI tract where SGLT1 is expressed and may offer an advantage over typical SGLT2 inhibitors, which are less effective in lowering blood glucose in patients with impaired renal function.(235b,236)
The thioglycoside MK-8719 (512) is a potent O-GlcNAcase (OGA) inhibitor that was advanced into clinical trials for the treatment of neurodegenerative disorders.(237) The hydroxymethyl-substituted, carbohydrate-based lead thiamet-G (511) showed poor membrane permeability and marginal brain exposure, consistent with its high TPSA value (105 Å2). Transformation of the hydroxymethyl substituent to a difluoromethyl moiety reduced the TPSA to the desirable range for CNS drugs (80 Å2), leading to the discovery of 512, which demonstrated good brain penetration, high metabolic stability, and other favorable pharmacokinetic properties. MK-8719 (512) was advanced into phase 1 clinical trials, although further development appears to have been abandoned.
Sodium taurocholate cotransporting polypeptide (NTCP), a membrane transporter that plays an important role in bile acid uptake, has been recognized as a cellular receptor for both hepatitis B virus (HBV) and hepatitis D virus (HDV).(238) Using a cell-based screening assay, cyclosporine A (CsA, 513), a cyclic peptide widely used in the clinic as an immunosuppressive agent for organ transplantation patients, was identified as a weak NTCP inhibitor, IC50 = 5.78 μM. In an effort to enhance NTCP inhibitory potency while minimizing the inherent immunosuppressive activity, a scaffold-hopping strategy involving a 1,4-ring closure was developed.(239) Cleavage of the olefin of 513 gave an aldehyde and cyclization with the pendent 4-hydroxyl functionality formed a hemiacetal, a versatile synthetic precursor to both acetals and hemithioacetals. The two hemithioacetals 514a and 514b, of undetermined absolute configuration, showed potent inhibition of HBV/HDV infection by specifically blocking NTCP, whereas their acetal counterparts were much less active. Unfortunately, the more active isomer 514b was the minor product from the reaction mixture, and purification proved to be challenging. Despite its size and molecular weight (MW = 1389), 514a exhibited oral bioavailability of 18% and a t1/2 of 5.8 h in mice, with a dose of 30 mg/kg administered by oral gavage providing protection of HDV-susceptible mice from an HDV infection. Importantly, the transformation of 513 to the (O,S)-acetal in 514a eliminated its immunosuppressive activity.

Thioacetals and Thioketals (R–S–C–S–R′)

Thioketals and thioacetals are considerably less susceptible to acid-mediated hydrolysis than ketals because sulfur is less prone to protonation than oxygen, and the intermediate carbenium/sulfonium ion is not adequately stabilized, as discussed above (Scheme 31).(240) Moreover, sulfur is a better nucleophile than oxygen, so it would be expected to more readily add back to the carbenium intermediate, particularly in the case of cyclic thioketals. In organic synthesis, acidic protocols for the removal of thioketals are typically nonproductive, and this motif is more commonly deprotected by treatment with Hg(II) salts or under oxidative conditions.(241) Hydrolytic stability studies conducted with benzophenone-based thioacetals in aqueous dioxane in the presence of perchloric acid have revealed that the diethyl thioketal is 104-fold more stable than the diethyl ketal but 104-fold less stable than the 1,3-dithiane derived from benzophenone.(240b)

Scheme 31

Scheme 31. Mechanism of the Acid-Catalyzed Hydrolysis of Thioketals
The identification of the first orally bioavailable angiotensin-converting enzyme (ACE) inhibitor captopril (516) in 1975 represented the first successful demonstration of rational, ligand-based drug design.(242) However, 516 is commonly associated with rash and taste disturbances that are attributed to the presence of the free thiol moiety, side effects addressed by enalaprilat (517), which was marketed as its ethyl ester prodrug enalapril (518).(243) Since the discovery of 516, more than 12 ACE inhibitors have been marketed, with spirapril (520), the ethyl ester prodrug of spiraprilat (519), the eighth ACE inhibitor to be launched in 1995.(244,245) The only structural difference between 518 and 520 is the presence of the spirocyclic thioketal ring in the latter and while both compounds have comparable potency and oral bioavailability, 520 exhibits a longer half-life. This is perhaps surprising based on the presence of the two sulfur atoms, which are potentially metabolically labile; however, they are actually quite stable toward metabolism with 519 the primary metabolite of 520.(246) Spiraprilat (519) was specifically designed to be eliminated through dual renal and hepatic clearance pathways, in contrast to most ACE inhibitors, which are subject to predominantly renal clearance; thus, sprirapril can be prescribed to patients with renal impairment.(246,247)
Probucol (521) is a prominent thioketal derivative that was advanced into clinical trials where it was evaluated for its antiatherogenic effects based on an interesting and complex underlying biochemical pharmacology.(248,249) Probucol (521) displays anti-inflammatory and antioxidant activities that contribute to its antiatherogenic properties and the compound also modestly reduces low-density lipoprotein (LDL)-associated cholesterol levels in vivo, although the two properties appear to be unrelated.(249) However, the clinical utility of 521 has been limited by a concomitant reduction in high-density lipoprotein (HDL)-associated cholesterol levels and QTc interval prolongation observed in some patients, and while used extensively in Japan, 521 was withdrawn in many markets with the arrival of statin-based cholesterol-lowering drugs.(248) Probucol (521) exhibits poor bioavailability and appears to be extensively metabolized including the spirocyclic bis-quinone 522, although available data on the metabolic fate appears to be sparse.(250)
Analogues of 521 have been extensively explored as orally bioavailable compounds. Succinobucol (523) is an anti-inflammatory and antioxidant agent that inhibits inducible VCAM-1 and MCP-1 expression and human aortic cell proliferation that was advanced into clinical trials to assess its potential in the treatment of atherosclerotic disease.(251) Succinobucol (523) is stable in aqueous CH3CN for extended periods (weeks) at room temperature and in mild acid or base where ester cleavage was of concern. However, the adjacent tert-butyl substituents are presumed to confer sufficient steric hindrance to protect the ester moiety such that 523 is not a prodrug of 521 in preclinical species and humans.(251) Succinobucol (523) was the major drug component in plasma following oral dosing of [14C]-labeled material to dogs and rats while 94–98% of drug-related material in the plasma of humans after oral administration was an unchanged parent. Subsequently, the alkylated acids 524 and 525 were advanced into clinical trials as anti-inflammatory agents designed to avoid the formation of the bis-quinone metabolite 522.(250)
ABC-99 (526) is the thioacetal analogue of doxofylline (64) that, like its progenitor, is an inhibitor of bronchospasm in vivo following oral administration believed to be a function of lung cAMP PDE inhibition and adenosine A2 agonism.(252) However, 526 is also mucolytic and exhibits antiinflammatory properties following oral dosing. When incubated with RLM for 30 min, 526 was the major material present, but the trans-sulfoxide 527 and the cis-sulfoxide 528 were identified as metabolites by careful comparison with authentic samples (Scheme 32).(252e) These metabolites appear to be the result of the action of flavin-containing monooxygenases (FMOs), and there was no evidence for the formation of bis-sulfoxides, sulfones, or, as observed with 64, hydroxylation at the thioacetal methine carbon, leading to ring opening.(252e)

Scheme 32

Scheme 32. Metabolism of 526 in RLM

(N,S)-Acetals and Ketals (R–N–C–S–R′)

(N,S)-Acetals are much more resistant to acid degradation than the corresponding (N,O)-acetals because the carbenium intermediate after the departure of the cationic amino group is less stable due to lack of stabilization from the adjacent sulfur atom relative to oxygen, as previously discussed. It has been estimated that a thiazolidine ring 529 (Scheme 33A) is more stable than an analogous oxazolidine ring 533 (Scheme 33B) by 4 orders of magnitude.(253) Thus, it took several hours to cleave thiazolidine 529 in aqueous TFA in contrast to just a few minutes for the oxazolidine homologue 533.(181a) The stability of (N,S)-acetals also depends on the nature of the C2 substituents: the dimethylthiazolidine 536 underwent ring opening in the presence of TFA within a few hours to give 537, while the unsubstituted analogue 538 was resistant to dissolution in strong acid (Scheme 34).(181a)

Scheme 33

Scheme 33. Mechanism of the Acid-Catalyzed Hydrolysis of (N,S)- (A) and (N,O)-Ketals (B)

Scheme 34

Scheme 34. Hydrolysis of 536537 and Structure of the Stable Analogue 538
An acylated (N,S)-acetal is a ubiquitous structural element in the penicillin and cephalosporin β-lactam antibiotics 539 and 541, respectively, exemplified by amoxicillin (540) and cephalexin (542).(254) β-Lactam antibiotics interrupt bacterial cell wall synthesis by inhibiting transpeptidases, the enzymes responsible for cross-linking peptides to form the peptidoglycan-based cell wall architecture.(255) Amoxicillin (540) and cephalexin (542) are two of the top ten prescribed antibiotics in the world. Both compounds show excellent oral bioavailability in humans, suggesting that the (N,S)-acetal has good chemical and metabolic stability despite the strain inherent to the fused ring system. Biotransformation studies of 540 in HLMs revealed seven metabolites which resulted from oxidation of one of the methyl substituents (543), which was further oxidized to 544 and 545, hydroxylation of the phenol (546), which underwent oxidative deamination of the primary amine to afford ketoamide 547, decarboxylation of the acid to give 548 and conjugation with glucuronic acid to afford 549 or 550 (the specific structures were not determined), as summarized in Scheme 35.(256) Thus, the (N,S)-acetal remained intact, and there was no indication of oxidation at sulfur, presumably due to the steric hindrance afforded by the adjacent geminal dimethyl substitution. Amoxicillin (540) incorporates a phenol, a potentially problematic group in drug design, should it be metabolized to a reactive quinone intermediate. However, in this case, no glutathione conjugates were detected in the HLM assay, suggesting that phenol oxidation to a quinone was not an issue. However, 540 and 542 display relatively short elimination half-lives in part due to their low protein binding.(257)

Scheme 35

Scheme 35. Metabolism of 540
The discovery of clavulanic acid (393) as an irreversible β-lactamase inhibitor in 1976 prompted an intensive search for other mechanistically related compounds, an effort that culminated in the identification of the penicillin-based sulfones exemplified by sulbactam (551), tazobactam (552), and (more recently) enmetazobactam (553).(258−261) The presence of the sulfone functionality appears to abolish inherent antibacterial activity in this chemotype but is important for β-lactamase inhibition by functioning as a leaving group similar to the oxygen atom in the (N,O)-hemiaminal element of 393. The mechanism of action of the penicillin-based sulfones involves ring opening of the thiazolidine 1,1-dioxide ring of 555 that is triggered by β-lactam ring opening to form the imine intermediate 556, which engages in a similar sequence of reactions to 393 to inactivate β-lactamase (Scheme 36).(258,261) The sole difference between 552 and 553 is the methylation of the triazole heterocycle in the latter, which results in the formation of a zwitterionic species that contributes to enhanced bacterial cell penetration. Enmetazobactam (553) is undergoing phase III clinical evaluation as part of combination therapy with β-lactam antibiotics for the treatment of serious Gram-negative infections.

Scheme 36

Scheme 36. Mechanism of β-Lactamase Inhibition by 554
The O-acylated intermediate 556 can hydrolyze to regenerate the active β-lactamase, a potential Achilles heel that was addressed by the pyridylmethylidene sulbactam 557, which was designed to subvert this pathway (Scheme 37A).(258a) Thus, nucleophilic addition of the pyridine nitrogen to the initially formed conjugated imine 558 to give 559, and subsequent aromatization furnished a highly stable indolizine adduct 560 that contributed to the observed enhanced inhibitory activity.(262) In order to rationalize the enzyme inhibition process, NaOMe was used as a surrogate for the serine of the enzyme (Scheme 37B). Thus, treatment of 561 with one equivalent of NaOMe in CH3OH at room temperature for 10 min gave indolizine 563, which was isolated in 85% yield after methylation to give 564. When tested with one E. coli β-lactamase, 557 demonstrated 100% inhibition at 1 μM compared to 81% inhibition for 393. In contrast, the phenyl analogue 565, which cannot react to form an indolizine adduct, was much less active (28% inhibition at 1 μM). Further modification of the geminal dimethyl groups led to LN-1–255 (566), which demonstrated significantly improved activity against several carbapenem-hydrolyzing class D β-lactamase enzymes (CHDLs) compared to 552.(263a) In a murine pneumonia model caused by carbapenem-resistant A. baumannii strains expressing carbapenem-hydrolyzing, class D β-lactamases, a combination of 566 with imipenem provided higher protection against pneumonia than the treatment with imipenem alone, suggesting that 566 may have potential to treat infections caused by A. baumannii isolates carrying CHDLs.(263b)

Scheme 37

Scheme 37. (A) Mechanism of β-Lactamase Inhibition by 557; (B) Reaction of 561 with Methoxide
Benzbromarone (567) is a highly effective uricosuric agent that was withdrawn from the market in several countries after reports of serious hepatotoxicity, likely due to the inhibition of mitochondrial function by metabolites.(264) In an attempt to mitigate mitochondrial inhibition, a series of aryl benzamides was explored, from which indoline 568 exhibited reduced mitochondrial inhibition while maintaining urate uptake inhibitory activity.(265a) However, the oral exposure of 568 in rats was significantly reduced (Cmax = 1.36 μg/mL compared to 4.42 μg/mL for 567) due to metabolic instability. Replacement of the core heterocycle with a benzothiazolidine dioxide in 569 resulted in enhanced exposure with a Cmax = 3.81 μg/mL. Benzothiazolidine dioxide 569 also exhibited a favorable CYP2C9 inhibition profile (IC50 = 57 μM compared to 41 nM for 567) but its urate uptake inhibitory activity was compromised. Optimization of the phenyl ring substitution pattern led to the identification of dotinurad (FYU-981, 570) as a potent, selective urate reabsorption inhibitor (urate transporter 1 inhibitor) for the treatment of hyperuricemia.(265a) Following oral administration of radiolabeled 570 to rats, cynomolgus monkeys, and humans, the major component in plasma was the parent drug (81.9, 92.0, and 80.9%, respectively), with the major metabolites like phenol sulfate, the 6-hydoxyl derivative, and 3,5-dichloro-4-hydroxy-benzoic acid, which are metabolites that were also observed in vitro along with the glucuronide of the phenol.(265b) The phenol glucuronide and phenol sulfate were the major metabolites detected in the urine of cynomolgus monkeys, while only small amounts (0.1–0.7%) of the metabolite reflecting loss of formaldehyde from the heterocyclic ring were observed in the in vitro and in vivo studies. Dotinurad (570) was approved in Japan in February 2020 as a new uricosuric medication for the treatment of hyperuricemia with or without gout.
TUG-1375 (573) is a potent and effective thiazolidine-based free fatty acid receptor 2 agonist (pKi = 6.7; cAMP pEC50 = 7.1, Emax = 86% relative to propionic acid) that has been explored as a tool molecule to assess its potential in the treatment of inflammatory and metabolic diseases.(266) The lead compound 571 that subtended the discovery of 573 was based on a 5-substituted proline core, a scaffolding element that interfered with efficient SAR studies due to the need for a complex, multistep synthesis. Using a bioisosteric replacement strategy based on the synthetically more tractable thiazolidine heterocycle exemplified by 572, a series of analogues was rapidly prepared and evaluated, an effort that led to the identification of 573 as a compound with favorable pharmaceutical and PK properties. Incubation of 573 in primary mouse hepatocytes revealed low intrinsic clearance (<8 μL/min/106 cells) with 81% of the parent compound remaining after 1 h and 72% preserved after 2 h, metabolic stability that subtended a t1/2 of 138 min following IV administration and 32% oral bioavailability. The (N,S)-acetal core also provided improved potency compared to the proline-based prototype while not posing a significant chemical stability issue.(266)
The proline-derived homophenylalanine derivative 574 was identified as a potent and highly selective DPP4 inhibitor (IC50 = 0.48 nM) but lacked oral bioavailability.(267a) By replacing the pyrrolidine ring with a thiazolidine, a new series of potent and selective DPP4 inhibitors was developed with 575, the most active analogue.(267b) This compound exhibited good metabolic stability in human and rat liver microsomes and was chemically stable at pH values ranging from 1 to 9 (>90% remaining after 24 h). The limited oral absorption of 575 was overcome by adopting the ethyl ester prodrug 576, which rapidly released 575 in the plasma, and oral administration of 576 to both rats and dogs elicited significant DPP4 inhibition.(267b)
Other prominent thiazolidine derivatives include the inhaled PDE4 inhibitor 577 for the treatment of respiratory disease and the gut-restricted agonist of G protein-coupled bile acid receptor 1 (GPBAR1, TGR5) 578 explored for potential in type II diabetes mellitus and inflammatory bowel disease.(268,269)

(N,N)-Aminals (R–N–C–N–R′)

Simple (N,N)-aminals are more susceptible to ring cleavage than homologous acetals and ketals, attributed to the ready protonation of the amine (580) that leads to a stable imine intermediate 581, which can hydrolyze to 532 via 582 (Scheme 38).(270) The stability of (N,N)-aminals can be enhanced by incorporating electron-withdrawing groups at C2 or acylating either or both of the basic amines. However, the effect on stability is context-dependent, as exemplified by the cyclic acylated aminal hetacillin (583), a prodrug of ampicillin (585), which is unstable in aqueous solution with a half-life of 15–30 min at 37 °C and pH = 7.(271) The geminal dimethyl groups at C2 contribute to the instability of 583 by stabilizing the carbonium ion intermediate 584 (Scheme 39).

Scheme 38

Scheme 38. Mechanism of the Acid-Catalyzed Hydrolysis of (N,N)-Aminals

Scheme 39

Scheme 39. Decomposition of 583 into 585
Pneumocandin B0 (586), also known as hydroxy echinocandin, displayed potent fungicidal activity, but its development was shelved because of a narrow spectrum of activity, insufficient solubility for IV formulation, and chemical instability due to the hemiaminal functionality.(272) Under basic conditions (pH > 8), the cyclic aminal of 586 is cleaved to give an aldehyde intermediate 587, which undergoes spontaneous ring closure to the thermodynamically more stable five-membered N-acyl hemiaminal 588 (Scheme 40). In the presence of acid (pH < 5), protonation of the hemiaminal amine followed by dehydration leads to a highly electrophilic N-acyliminium intermediate 589, which can react with a variety of nucleophiles. When no external nucleophile is available, intramolecular attack by the amide nitrogen occurs to form another aminal 590. Both degradation products are significantly less active than the original natural product.(272b)

Scheme 40

Scheme 40. Structure of 586 and Degradation Pathways under Basic and Acidic Conditions
In an attempt to stabilize the hemiaminal of 586, a cationic aminoethyl ether group was incorporated to form the (N,O)-aminal 591.(273) The amino side chain was beneficial to both the antifungal activity and solubility, which was further increased upon reduction of the primary amide to the amine 592. Diamine analogue 592 exhibited enhanced inhibitory activity toward both Candida and Aspergillus spp., was highly water-soluble and considerably more stable than 586.(273) Nevertheless, the plasma exposure of 592 was poor in the chimpanzee, a good predictor of human PK, and its toxicological profile was of concern (acute toxicity = 30 mpk in mice with an inadequate safety margin). Both issues were circumvented by simply switching from the (N,O)-aminal to the (N,N)-aminal found in caspofungin (593) which showed a 2- to 3-fold improvement in the chimpanzee PK profile over the matched oxygen analogue.(274) Moreover, the acute toxicity of 593 in mice was mitigated, with the tolerated dose increased to 50 mpk, which provided adequate separation from the efficacious dose. The favorable PK profile of 593 was consistent across other preclinical species, with sustained plasma levels and an elimination t1/2 of 9–11 h in humans supporting a once-daily IV dosing regimen.(274) With an optimized formulation, 593 has a 2-year shelf life at 2–8 °C and was the first of the echinocandin class of antifungal agents to be approved in the U.S. to treat invasive aspergillosis after the failure of standard therapy, and it has become one of the most prescribed IV antifungal agents worldwide.(272a)
The isoxazolinone 594 is representative of a series of antibacterial agents modeled after linezolid (595) but which simplifies the structure by removing a chiral center.(275) Chemical stability was of concern, but representative compounds demonstrated excellent stability when exposed to TFA in CH2Cl2 and 1 N HCl in THF, while <1% degradation was observed over 18 h when dissolved in citrate buffer at pH = 4. Under basic conditions at pH = 8.5, the molecules were labile, with loss of the acetamidomethyl moiety occurring in a fashion that was time- and temperature-dependent and amounted to 40% degradation over 18 h. This is presumably a base-catalyzed elimination that reflects the inherent acidity of the isoxazolinone heterocycle, which has a pKa estimated to be <6 based on the value measured for the naphthalene derivative 596.(276) However, solid-state stability was high, with no detectable erosion of compound integrity over 3 years at an ambient temperature. Several members of this chemotype demonstrated oral bioavailability in mice and rats and were active in a mouse model of S. aureus infection following oral administration.(275)
Another prominent drug that integrates an (N,N)-aminal moiety is baloxavir (602) which is marketed as its prodrug baloxavir marboxil (603), the first new influenza antiviral agent approved by the FDA in nearly 20 years.(277) Unlike neuraminidase inhibitors, which prevent nascent virus release from host cells, 602 directly prevents virus replication by inhibiting the cap-dependent endonuclease (CEN) activity of the viral polymerase.(277) The carbamoyl pyridone bicyclic core originated with the weak CEN inhibitor screening lead 597 that lacked a hydrophobic domain, a deficiency that was addressed by the introduction of a benzhydryl moiety to afford 598, which exhibited markedly enhanced CEN inhibitory activity and antiviral potency.(277b) The carboxylic acid was subsequently eliminated to increase membrane permeability and the methoxymethyl side chain replaced with an isopropyl group to address a metabolic soft spot. The resulting analogue 599 exhibited good antiviral potency with an EC50 value of 58 nM in a cytopathic effect (CPE)-based antiviral assay, but the rat IV clearance for this molecule was high (25 mL/min/kg), attributed to a high free fraction in rat plasma (fu = 18%) rather than metabolic instability (79% remaining after 30 min in RLM). A common approach to increase protein binding is to add hydrophobic groups; however, this tactic can adversely impact both biological activity and metabolic stability. To reduce the free fraction while maintaining the other favorable properties, a judicious bioisosteric replacement approach was embraced. Substitution of the C-1 methine with a nonbasic nitrogen atom (due to the α effect) to form a cyclic aminal increased cLogP by 1.4 units, which contributed to a significant reduction in the free fraction from 18% to 3.8% while preserving potent antiviral activity. The metabolic stability of the cyclic aminal was confirmed in RLM, with 86% remaining after 30 min compared to 79% for the C-1 analogue, while IV clearance in the rat decreased from 25 to 11 mL/min/kg. Switching the lipophilic group at N-1 from the acyclic benzhydryl to the cyclic dihydrodibenzothiepine 600 improved antiviral activity by 4-fold; however, this was accompanied by a 3-fold increase in rat IV clearance because of lower metabolic stability and a higher free fraction. Installing a trifluoro-2-propyl substituent at N-3 and doubly fluorinating one of the phenyl rings located in the lipophilic region improved the in vitro and in vivo profile.(278) These efforts led to the discovery of 601 with excellent antiviral activity as well favorable rat IV clearance. In a mouse model of influenza virus infection, 601 showed potent oral efficacy in reducing virus titers in the lung. Simultaneous optimization at N-3 and C-2 culminated in the discovery of 602, which was developed as the prodrug of 603 for the treatment of influenza A and influenza B infections.(277) The prodrug exhibits favorable pharmacokinetic characteristics, including a half-life of 79 h in humans, supporting single daily oral dosing.(279)
An acylated five-membered (N,N)-aminal core was designed as part of the optimization of a series of HIV-1 integrase inhibitors in which a ring fusion was introduced to the bicyclic core of the lead compound 604 in an effort to balance potency and PK properties.(280) These efforts led to spiroaminal 605, which demonstrated excellent intrinsic antiviral activity (wild-type (WT) IC50 = 2.5 nM without human serum) but which was subject to an unacceptably large shift in potency in the presence of human serum (WT IP IC50 = 600 nM with 50% normal human serum, a 240-fold shift), attributed to high protein binding. Incorporation of the polar hydroxyl groups in 606 and 607 reduced protein binding and led to an increase in potency in the presence of serum. However, the hydroxyl group was still not sufficient to provide the desired solubility and permeability, so a double prodrug approach was adopted in the context of 608.(280) Of particular note, no decomposition of the acylated aminal functionality was observed with any of these analogues.
Tomivosertib (eFT508, 612) is an orally bioavailable, potent, and selective inhibitor of mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) that is currently in phase II clinical trials in patients with advanced castrate-resistant prostate cancer.(281) One of the early lead compounds that contributed to the discovery of 612 was the lactam 609, which exhibited moderate dual inhibition of MNK1/2 but lacked adequate kinase selectivity. Thus, an effort was made to target one of the atypical residues in the ATP binding site of MNK1/2, the pre-DFG residue Cys225. Attempts to capture Cys225 with an unsaturated amide Michael acceptor had not been successful, indicative of low reactivity leading to a focus on engaging this residue in a stereoelectronic interaction as a means of enhancing both potency and selectivity. To this end, the lactam was replaced with a pyridone-aminal where the newly introduced lactam carbonyl in 610 engaged in a multipolar interaction with the Cys225 thiol. This kind of stereoelectronic interaction, in which electron density is donated into the amide C═O π* orbital and is described as multipolar in nature, is optimal when the electron donor approaches at the Bürgi-Dunitz angle (Figure 23A).(282) An X-ray cocrystal structure of 610 bound to MNK2 confirmed the design based on the distance and angle between the Cys225 sulfur atom and the carbonyl carbon atom (Figure 23B). The cyclic aminal proved to be essential as the ring-opened product 613 lost activity, in part due to a less than optimal geometry for the Bürgi–Dunitz-type of interaction, although the phenyl homologue 614 was more potent. As anticipated by the design principle, 610 showed significant improvement over 609 in the kinase selectivity profile (>400 kinases), and a similar trend was observed in other pyridone–benzene pairs. Because of its favorable selectivity profile, facile synthesis, and excellent chemical stability, the pyridone-aminal series was prioritized for further optimization. 2-Methyl pyrimidine substitution increased cellular potency by 23-fold (611), while further amino substitution at C6 further improved potency leading to tomivosertib (612). Comparison of the X-ray cocrystal structures of 610 and 612 bound to MNK2 suggested that the Bürgi–Dunitz interaction in the latter was stronger, which may contribute to its superior potency (Figure 23B,C).(281)

Figure 23

Figure 23. (A) The Bürgi–Dunitz angle for the approach of a nucleophile to the carbon atom of a carbonyl moiety; (B) details surrounding the interaction of the thiol of Cys225 with 610; (C) details associated with the interaction of the thiol of Cys225 with 612.

Trazpiroben (615, TAK-906) is an orally bioavailable, second-generation dual dopamine D2/D3 receptor antagonist that is currently in phase IIb clinical studies for the treatment of diabetic and idiopathic gastroparesis, a disease in which stomach emptying is compromised.(283) The cyclic, acylated aminal moiety that is spiroannulated to a piperidine heterocycle and the carboxylic acid moiety are unique structural elements that differentiate 615 from the first-generation medications metoclopramide (617) and domperidone (618), and the second-generation clinical compound metopimazine (NG101, 619).(284,285) Due to its zwitterionic nature, 615 showed marginal brain penetration in rat and dog studies and exhibited low affinity for the hERG channel with IC50 of 15.6 μM, suggesting reduced potential for both the CNS and cardiovascular side effects that have been associated with the first-generation dual dopamine D2/D3 receptor antagonists, which are limited to short-term treatment. In healthy volunteers, 615 exhibited rapid oral absorption and elimination (tmax = ∼1.1 h; t1/2 = 4–11 h) after single and multiple doses.(284) The major metabolite in human plasma was the alcohol 616.(286)In vitro biotransformation studies using human, rat, and dog hepatocytes identified a non-CYP pathway as the primary route of metabolism (57%), which involves multiple cytosolic, NADPH-dependent reductases, including aldo-keto reductase, and short-chain dehydrogenase/reductase, which reduce the ketone moiety of 615 to afford 616. The remainder of the metabolism of 615 is mediated by CYP3A4 and CYP2C8 (43%); however, cleavage of the acylated cyclic aminal does not appear to an issue based on the available data.(286)
An identical fused tricyclic acylated aminal core is present in both 620, a lead inhibitor of respiratory syncytial virus (RSV) fusion, and ML375 (621), the first M5-selective and brain penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor.(287a,288) The M5-NAM activity of 621 was found to depend upon the absolute configuration of the chiral center with the enantiomeric 622 inactive. Optimization of the RSV activity in 617 focused on improving the pharmaceutical properties and PK profile and culminated in the identification of BTA9881 (623), a single enantiomer that was advanced into phase 1 clinical studies.(287b) In this series, the antiviral activity was also dependent on the absolute configuration of the chiral center with the antipode 624 inactive.(287b)

Conclusion

ARTICLE SECTIONS
Jump To

Geminal diheteroatomic motifs have found gainful application in drug design and discovery where their unique properties have been successfully utilized to restrict conformation, increase potency and selectivity, improve pharmaceutical properties, mitigate ion channel activity, and provide structural novelty. Despite the general perception about the liability of acetals and ketals toward gastric acid during oral absorption, simple acetal- and ketal-containing compounds can possess sufficient acid stability and metabolic stability to deliver adequate oral bioavailability in preclinical species and humans. Where stability issues arise, an understanding of the fundamental of the underlying organic chemistry provides a basis for the implementation of rational approaches to mitigate problems. These approaches include the incorporation of electron-withdrawing substituents at sites that exert a direct effect upon the diheteroatomic motif and the introduction of proximal basic heteroaryl rings or amines. Conformational rigidification can also serve as an effective strategy to stabilize diheteroatomic motifs, an approach that has been adopted by Nature in the construction of penicillin and cephalosporin β-lactam antibiotics. The less stable cyclic (N,N)- and (N,O)-based aminals generally require a nonbasic amine component which can be achieved by either introducing an electron-withdrawing substituent, most commonly an acyl group, or by incorporating the nitrogen atom into a heteroaryl ring system as exemplified by nucleoside and nucleotide analogues. The acid-stable cyclic (O,S) motif can deliver unique conformational attributes compared to an acetal or ketal, which can result in unexpected pharmacological and PK properties, demonstrated most effectively by the nucleoside analogue lamivudine (497). Most conveniently, geminal heteroatomic motifs can often be readily prepared from simple carbonyl-containing precursors, and their tolerability toward acidic conditions can easily be evaluated in vitro and in simulated gastric acid preparations at 37 °C. Against the backdrop of the successful discovery and development of numerous orally bioavailable drugs that incorporate a broad range of geminal diheteratomic motifs, a refined understanding of their physicochemical properties enables the design and deployment of these structural elements in a fashion that can fully exploit their unique properties. It is hoped that by creating a heightened awareness and understanding of geminal diheteratomic motifs, rather than being viewed as unconventional and problematic, their utility and judicious application in drug discovery will be facilitated.

Author Information

ARTICLE SECTIONS
Jump To

  • Corresponding Authors
    • Notes
      The authors declare no competing financial interest.

    Biographies

    ARTICLE SECTIONS
    Jump To

    Yong-Jin Wu

    Yong-Jin Wu obtained his Ph.D. in organic chemistry from the Memorial University of Newfoundland in 1991 under the guidance of Prof. Jean Burnell. Subsequently, he undertook 3 years of postdoctoral training in natural product synthesis with Prof. Derrick Clive at the University of Alberta and Prof. E. J. Corey at Harvard University. He started his career as a medicinal chemist at Pfizer Central Research in Groton, CT, in 1995 and joined Bristol Myers Squibb (BMS) in Wallingford, CT, in 1999. He has been working at BMS ever since and is currently at the Cambridge, MA facility, where his investigations focus on the discovery of novel kinase inhibitors for immunology, rheumatology, and oncology indications.

    Nicholas A. Meanwell

    Nicholas A. Meanwell received his Ph.D. from the University of Sheffield and conducted postdoctoral studies at Wayne State University before joining BMS in 1982. He has been associated with the discovery of BMY-433771, an inhibitor of respiratory syncytial virus fusion, the HIV-1 attachment inhibitor temsavir/fostemsavir, the HIV-1 maturation inhibitor GSK-3532795/BMS-955176, and the marketed HCV inhibitors asunaprevir (NS3), daclatasvir (NS5A), and beclabuvir (NS5B). He is the corecipient of a 2014 PhRMA Research and Hope Award for Biopharmaceutical Industry Research and a 2017 ACS Heroes of Chemistry Award. He was the recipient of the 2015 Philip S. Portoghese Medicinal Chemistry Lectureship Award and was inducted into the ACS Division of Medicinal Chemistry Hall of Fame in 2015.

    Acknowledgments

    ARTICLE SECTIONS
    Jump To

    We would like to thank our colleagues Brian Venables and Matthew Patton of Bristol Myers Squibb Research and Early Development, Cambridge, MA, for reviewing the manuscript.

    Abbreviations Used
    5HT

    5-hydroxytryptamine

    5-LO

    5-lipoxygenase

    ACAT

    acyl-CoA:cholesterol O-acyltransferase

    ACE

    angiotensin-converting enzyme

    ADC

    antibody–drug conjugate

    AEA

    anandamide

    AIDS

    acquired immunodeficiency syndrome

    ALL

    acute lymphocytic leukemia

    AML

    acute myeloid leukemia

    ATP

    adenosine triphosphate

    BRD

    bovine respiratory disease

    BTAa

    Bicycles from Tartaric acid and Amino acids

    CB

    cannabinoid

    CEN

    cap-dependent endonuclease

    CFTR

    cystic fibrosis transmembrane regulator

    CNS

    central nervous system

    COPD

    chronic obstructive pulmonary disease

    CPE

    cytopathic effect

    cpKa

    calculated pKa

    CSD

    Cambridge Structural Database

    CSF

    cerebrospinal fluid

    Cyp

    cyclophilin

    CYP450

    cytochrome P450

    DAT

    dopamine transporter

    DDI

    drug–drug interaction

    DMAc

    dimethylacetamide

    DHA

    dihydroartemisinin

    DMSO

    dimethyl sulfoxide

    DNA

    DNA

    FAAH

    fatty acid amide hydrolase

    FDA

    United States Food and Drug Administration

    FMO

    flavin-dependent monooxygenase

    FRET

    fluorescence resonance energy transfer

    Fsp3

    fraction of sp3 carbon atoms

    GABA

    γ-aminobutyric acid

    GAE

    general anomeric effect

    GI

    gastrointestinal

    GlyT1

    glycine transporter

    GT

    genotype

    HBD

    H-bond donor

    HCV

    hepatitis C virus

    hERG

    human ether-à-go-go-related gene

    HIV-1

    human immunodeficiency virus-1

    HLM

    human liver microsomes

    HPMN

    human peripheral blood polymorphonuclear monocyte

    HPV

    human papilloma virus

    HWB

    human whole blood

    MAP kinase

    mitogen-activated protein kinase

    MRSA

    methicillin-resistant S. aureus

    MSSA

    methicillin-susceptible S. aureus

    NBTI

    novel bacterial topoisomerase inhibitors

    NHV

    normal healthy volunteer

    NK1

    neurokinin-1

    NMP

    N-methyl pyrrolidone

    OEA

    oleoylethanolamide

    OGA

    O-GlcNAcase

    OX

    orexin

    PDE

    phosphodiesterase

    PEA

    palmitoylethanolamide

    PEG

    polyethylene glycol

    PK

    pharmacokinetic

    PPAR

    peroxisome proliferator-activated receptor

    PXR

    pregnane X receptor

    RLM

    rat liver microsomes

    RNAP

    DNA-dependent RNA polymerase

    RSV

    respiratory syncytial virus

    S1P1

    sphingosine-1-phosphate receptor 1

    SCW

    streptococcal cell wall

    SERT

    serotonin transporter

    SGLT

    sodium–glucose-linked transporter

    SP

    substance P

    SPIDER

    substance P-induced dermal inflammation

    SSTR

    somatostatin receptor

    TAMRA

    tetramethylrhodamine

    TFA

    trifluoroacetic acid

    THF

    tetrahydrofuran

    TPSA

    topological polar surface area

    TxA2

    thromboxane A2

    U.S.

    United States of America

    WHO

    World Health Organization

    WT

    wild-type.

    References

    ARTICLE SECTIONS
    Jump To

    This article references 288 other publications.

    1. 1
      McLay, I. M.; Halley, F.; Souness, J. E.; McKenna, J.; Benning, V.; Birrell, M.; Burton, B.; Belvisi, M.; Collis, A.; Constan, A.; Foster, M.; Hele, D.; Jayyosi, Z.; Kelley, M.; Maslen, C.; Miller, G.; Ouldelhkim, M. C.; Page, K.; Phipps, S.; Pollock, K.; Porter, B.; Ratcliffe, A. J.; Redford, E. J.; Webber, S.; Slater, B.; Thybaud, V.; Wilsher, N. The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy. Bioorg. Med. Chem. 2001, 9, 537554,  DOI: 10.1016/S0968-0896(00)00331-X
    2. 2
      Ndubaku, C. O.; Crawford, J. J.; Drobnick, J.; Aliagas, I.; Campbell, D.; Dong, P.; Dornan, L. M.; Duron, S.; Epler, J.; Gazzard, J.; Heise, C. E.; Hoeflich, K. P.; Jakubiak, D.; La, H.; Lee, W.; Lin, B.; Lyssikatos, J. P.; Maksimoska, J.; Marmorstein, R.; Murray, L. J.; O’Brien, T.; Oh, A.; Ramaswamy, S.; Wang, W.; Zhao, X.; Zhong, Y.; Blackwood, E.; Rudolph, J. Design of selective PAK1 inhibitor G-5555: improving properties by employing an unorthodox low pKa polar moiety. ACS Med. Chem. Lett. 2015, 6, 12411246,  DOI: 10.1021/acsmedchemlett.5b00398
    3. 3
      Khulbe, P.; Shrivastava, B.; Sharma, P.; Tiwari, A. K. In-situ buffered formulation: an effective approach for acid labile drug. Int. J. Pharm. Sci. Res. 2017, 8, 3544,  DOI: 10.13040/IJPSR.0975-8232.8(1).35-44
    4. 4
      Minchin, S.; Lodge, J. Understanding biochemistry: structure and function of nucleic acids. Essays Biochem. 2019, 63, 433456,  DOI: 10.1042/EBC20180038
    5. 5
      Stallforth, P.; Lepenies, B.; Adibekian, A.; Seeberger, P. H. Carbohydrates: a frontier in medicinal chemistry. J. Med. Chem. 2009, 52, 55615577,  DOI: 10.1021/jm900819p .
      (b) Ernst, B.; Magnani, J. L. From carbohydrate leads to glycomimetic drugs. Nat. Rev. Drug Discovery 2009, 8, 661677,  DOI: 10.1038/nrd2852 .
      (c) Galan, M. C.; Benito-Alifonso, D.; Watt, G. M. Carbohydrate chemistry in drug discovery. Org. Biomol. Chem. 2011, 9, 35983610,  DOI: 10.1039/c0ob01017k
    6. 6
      Wolfenden, R. Benchmark reaction rates, the stability of biological molecules in water, and the evolution of catalytic power in enzymes. Annu. Rev. Biochem. 2011, 80, 645667,  DOI: 10.1146/annurev-biochem-060409-093051
    7. 7
      (a) Beard, W. A.; Horton, J. K.; Prasad, R.; Wilson, S. H. Eukaryotic base excision repair: new approaches shine light on mechanism. Annu. Rev. Biochem. 2019, 88, 137162,  DOI: 10.1146/annurev-biochem-013118-111315 .
      (b) Drohat, A. C.; Maiti, A. Mechanisms for enzymatic cleavage of the N-glycosidic bond in DNA. Org. Biomol. Chem. 2014, 12, 83678378,  DOI: 10.1039/C4OB01063A
    8. 8
      Vocadlo, D. J.; Davies, S. G. Mechanistic insights into glycosidase chemistry. Curr. Opin. Chem. Biol. 2008, 12, 539555,  DOI: 10.1016/j.cbpa.2008.05.010
    9. 9
      (a) Yu, S.; Oh, J.; Li, F.; Kwon, Y.; Cho, H.; Shin, J.; Lee, S. K.; Kim, S. New scaffold for angiogenesis inhibitors discovered by targeted chemical transformations of wondonin natural products. ACS Med. Chem. Lett. 2017, 8, 10661071,  DOI: 10.1021/acsmedchemlett.7b00281 .
      (b) Huang, Z.; Williams, R. B.; Martin, S. M.; Lawrence, J. A.; Norman, V. L.; O’Neil-Johnson, M.; Harding, J.; Mangette, J. E.; Liu, S.; Guzzo, P. R.; Starks, C. M.; Eldridge, G. R. Bifidenone: structure-activity relationship and advanced preclinical candidate. J. Med. Chem. 2018, 61, 67366747,  DOI: 10.1021/acs.jmedchem.7b01644 .
      (c) Corey, E. J.; Wu, Y-. J. Total synthesis of (±)-paeoniflorigenin and paeoniflorin. J. Am. Chem. Soc. 1993, 115, 88718872,  DOI: 10.1021/ja00072a063 .
      (d) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. Total synthesis of halichondrin B and norhalichondrin B. J. Am. Chem. Soc. 1992, 114, 31623164,  DOI: 10.1021/ja00034a086 .
      (e) Fattorusso, C.; Persico, M.; Calcinai, B.; Cerrano, C.; Parapini, S.; Taramelli, D.; Novellino, E.; Romano, A.; Scala, F.; Fattorusso, E.; Taglialatela-Scafati, O. Manadoperoxides A-D from the Indonesian sponge Plakortis cfr. simplex. Further insights on the structure-activity relationships of simple 1,2-dioxane antimalarials. J. Nat. Prod. 2010, 73, 11381145,  DOI: 10.1021/np100196b .
      (f) Chevallier, O. P.; Graham, S. F.; Alonso, E.; Duffy, C.; Silke, J.; Campbell, K.; Botana, L. M.; Elliott, C. T. New insights into the causes of human illness due to consumption of azaspiracid contaminated shellfish. Sci. Rep. 2015, 5, 9818,  DOI: 10.1038/srep09818 .
      (g) Allan, K.; Stoltz, B. M. A concise total synthesis of (−)-quinocarcin via aryne annulation. J. Am. Chem. Soc. 2008, 130, 1727017271,  DOI: 10.1021/ja808112y .
      (h) Feng, X.; Bello, D.; Lowe, P. T.; Clark, J.; O’Hagan, D. Two 30-O-β-glucosylated nucleoside fluorometabolites related to nucleocidin in Streptomyces calvus. Chem. Sci. 2019, 10, 95019505,  DOI: 10.1039/C9SC03374B .
      (i) Whitley, R.; Alford, C.; Hess, F.; Buchanan, R. Vidarabine: a preliminary review of its pharmacological properties and therapeutic use. Drugs 1980, 20, 267282,  DOI: 10.2165/00003495-198020040-00002 .
      (j) Mazumder, A.; Dwivedi, A.; du Plessis, J. Sinigrin and its therapeutic benefits. Molecules 2016, 21, 416,  DOI: 10.3390/molecules21040416 .
      (k) Kim, C. S.; Oh, J.; Subedi, L.; Kim, S. Y.; Choi, S. U.; Lee, K. R. Rare thioglycosides from the roots of Wasabia japonica. J. Nat. Prod. 2018, 81, 21292133,  DOI: 10.1021/acs.jnatprod.8b00570 .
      (l) Igarashi, Y.; Asano, D.; Sawamura, M.; In, Y.; Ishida, T.; Imoto, M. Ulbactins F and G, polycyclic thiazoline derivatives with tumor cell migration inhibitory activity from Brevibacillus sp. Org. Lett. 2016, 18, 16581661,  DOI: 10.1021/acs.orglett.6b00531 .
      (m) Iwasa, E.; Hamashima, Y.; Fujishiro, S.; Higuchi, E.; Ito, A.; Yoshida, M.; Sodeoka, M. Total synthesis of (+)-chaetocin and its analogues: their histone methyltransferase G9a inhibitory activity. J. Am. Chem. Soc. 2010, 132, 40784079,  DOI: 10.1021/ja101280p .
      (n) Zipperer, A.; Konnerth, M.; Laux, C.; Berscheid, A.; Janek, D.; Weidenmaier, C.; Burian, M.; Schilling, N. A.; Slavetinsky, C.; Marschal, M.; Willmann, M.; Kalbacher, H.; Schittek, B.; Brötz-Oesterhelt, H.; Grond, S.; Peschel, A.; Krismer, B. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 2016, 535, 511516,  DOI: 10.1038/nature18634 .
      (o) Foo, K.; Newhouse, T.; Mori, I.; Takayama, H.; Baran, P. S. Total synthesis guided structure elucidation of (+)-psychotetramine. Angew. Chem., Int. Ed. 2011, 50, 27162719,  DOI: 10.1002/anie.201008048 .
      (p) Ohyabu, N.; Nishikawa, T.; Isobe, M. First asymmetric total synthesis of tetrodotoxin. J. Am. Chem. Soc. 2003, 125, 87988805,  DOI: 10.1021/ja0342998
    10. 10
      (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015, 58, 83158359,  DOI: 10.1021/acs.jmedchem.5b00258 .
      (b) Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 2018, 61, 58225880,  DOI: 10.1021/acs.jmedchem.7b01788 .
      (c) Liu, B.; Thayumanavan, S. Substituent effects on the pH sensitivity of acetals and ketals and their correlation with encapsulation stability in polymeric nanogels. J. Am. Chem. Soc. 2017, 139, 23062317,  DOI: 10.1021/jacs.6b11181
    11. 11
      (a) Gillies, E. R.; Goodwin, A. P.; Fréchet, J. M. Acetals as pH-sensitive linkages for drug delivery. Bioconjugate Chem. 2004, 15, 12541263,  DOI: 10.1021/bc049853x .
      (b) Gillies, E. R.; Fréchet, J. M. pH-Responsive copolymer assemblies for controlled release of doxorubicin. Bioconjugate Chem. 2005, 16, 361368,  DOI: 10.1021/bc049851c .
      (c) Huang, F.; Cheng, R.; Meng, F.; Deng, C.; Zhong, Z. Micelles based on acid degradable poly(acetal urethane): preparation, pH-sensitivity, and triggered intracellular drug release. Biomacromolecules 2015, 16, 22282236,  DOI: 10.1021/acs.biomac.5b00625 .
      (d) Cui, L.; Cohen, J. L.; Chu, C. K.; Wich, P. R.; Kierstead, P. H.; Fréchet, J. M. Conjugation chemistry through acetals toward a dextran-based delivery system for controlled release of siRNA. J. Am. Chem. Soc. 2012, 134, 1584015848,  DOI: 10.1021/ja305552u .
      (e) Hong, B. J.; Chipre, A. J.; Nguyen, S. T. Acid-degradable polymer-caged lipoplex (PCL) platform for siRNAdelivery: facile cellular triggered release of siRNA. J. Am. Chem. Soc. 2013, 135, 1765517658,  DOI: 10.1021/ja404491r .
      (f) Broaders, K. E.; Cohen, J. A.; Beaudette, T. T.; Bachelder, E. M.; Fréchet, J. M. Acetalated dextran is a chemically and biologically tunable material for particulate immunotherapy. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 54975502,  DOI: 10.1073/pnas.0901592106 .
      (g) Lee, S.; Wang, W.; Lee, Y.; Sampson, N. S. Cyclic acetals as cleavable linkers for affinity capture. Org. Biomol. Chem. 2015, 13, 84458452,  DOI: 10.1039/C5OB01056J
    12. 12
      Maryanoff, B. E. Phenotypic assessment and the discovery of topiramate. ACS Med. Chem. Lett. 2016, 7, 662665,  DOI: 10.1021/acsmedchemlett.6b00176
    13. 13
      Hale, J. L.; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. M.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. Structural optimization affording2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J. Med. Chem. 1998, 41, 46074614,  DOI: 10.1021/jm980299k
    14. 14
      Delost, M. D.; Smith, D. T.; Anderson, B. J.; Njardarson, J. T. From oxiranes to oligomers: architectures of U.S. FDA approved pharmaceuticals containing oxygen heterocycles. J. Med. Chem. 2018, 61, 1099611020,  DOI: 10.1021/acs.jmedchem.8b00876
    15. 15
      (a) De Wolfe, R. H.; Ivanetich, K. M.; Perry, N. F. General acid catalysis in benzophenone ketal hydrolysis. J. Org. Chem. 1969, 34, 848854,  DOI: 10.1021/jo01256a015 .
      (b) Fife, T. H. General acid catalysis of acetal, ketal, and ortho ester hydrolysis. Acc. Chem. Res. 1972, 5, 264272,  DOI: 10.1021/ar50056a002 .
      (c) Cordes, E. H.; Bull, H. G. Mechanism and catalysis for hydrolysis of acetals, ketals, and ortho esters. Chem. Rev. 1974, 74, 581603,  DOI: 10.1021/cr60291a004 .
      (d) Wasserman, H. H.; Clark, G. M.; Turley, P. C. Recent aspects of cyclopropanone chemistry. In: Stereochemistry I. Topics in Current Chemistry Fortschritte der Chemischen Forschung 1974, 47, 73156,  DOI: 10.1007/3-540-06648-9_9 .
      (e) Deslongchamps, P.; Dory, Y. L.; Li, S. The relative rate of hydrolysis of a series of acyclic and six-membered cyclic acetals, ketals, orthoesters, and orthocarbonates. Tetrahedron 2000, 56, 35333537,  DOI: 10.1016/S0040-4020(00)00270-2 .
      (f) Li, S.; Dory, Y. L.; Deslongchamps, P. On the relative rate of hydrolysis of a series of ketals and their proton affinities. Isr. J. Chem. 2000, 40, 209215,  DOI: 10.1560/QRH5-Q3N0-0XA6-PT9Y .
      (g) Repetto, S. L.; Costello, J. F.; Butts, C. P.; Lam, J. K. W.; Ratcliffe, N. M. The hydrolysis of geminal ethers: a kinetic appraisal of orthoesters and ketals. Beilstein J. Org. Chem. 2016, 12, 14671475,  DOI: 10.3762/bjoc.12.143 .
      (h) Salomaa, P.; Kankaanpera, A.; Norin, T. The hydrolysis of 1,3-dioxolan and its alkyl-substituted derivatives. Part I. the structural factors influencing the rates of hydrolysis of a series of methyl-substituted dioxolans. Acta Chem. Scand. 1961, 15, 871878,  DOI: 10.3891/acta.chem.scand.15-0871 .
      (i) Jacques, S. A.; Leriche, G.; Mosser, M.; Nothisen, M.; Muller, C. D.; Remy, J.-S.; Wagner, A. From solution to in-cell study of the chemical reactivity of acid sensitive functional groups: a rational approach towards improved cleavable linkers for biospecific endosomal release. Org. Biomol. Chem. 2016, 14, 47944803,  DOI: 10.1039/C6OB00846A
    16. 16
      Blanco-Ania, D.; Rutjes, F. P. J. T. Carbonylonium ions: the onium ions of the carbonyl group. Beilstein J. Org. Chem. 2018, 14, 25682571,  DOI: 10.3762/bjoc.14.233
    17. 17
      (a) Fife, T. H.; Hagopian, L. Steric effects in ketal hydrolysis. J. Org. Chem. 1966, 31, 17721775,  DOI: 10.1021/jo01344a024 .
      (b) McClelland, R. A.; Watada, B.; Lew, C. S. Q. Reversibility of the ring-opening step in the acid hydrolysis of cyclic acetophenone acetals. J. Chem. Soc., Perkin Trans. 2 1993, 17231727,  DOI: 10.1039/p29930001723 .
      (c) Knowles, J. P.; Whiting, A. The effects of ring size and substituents on the rates of acid-catalysed hydrolysis of five- and six-membered ring cyclic ketone acetals. Eur. Eur. J. Org. Chem. 2007, 2007, 33653368,  DOI: 10.1002/ejoc.200700244 .
      (d) Liu, B.; Thayumanavan, S. Substituent effects on the pH sensitivity of acetals and ketals and their correlation with encapsulation stability in polymeric nanogels. J. Am. Chem. Soc. 2017, 139, 23062317,  DOI: 10.1021/jacs.6b11181
    18. 18
      Miller, S. R.; Krasutsky, S.; Kiprof, P. Stability of carboxonium ions. J. Mol. Struct.: THEOCHEM 2004, 674, 4347,  DOI: 10.1016/j.theochem.2003.12.044
    19. 19
      Carey, F. A.; Sundberg, R. J. Reaction of Carbonyl Compounds. Advanced Organic Chemistry 1977, 325360,  DOI: 10.1007/978-1-4613-9792-2_8
    20. 20
      (a) Guthrie, J. P. Carbonyl addition reactions. Factors affecting the hydrate-hemiacetal and hemiacetal-acetal equilibrium constants. Can. J. Chem. 1975, 53, 898906,  DOI: 10.1139/v75-125 .
      (b) Greenzaid, P.; Luz, Z.; Samuel, D. A nuclear magnetic resonance study of the reversible hydration of aliphatic aldehydes and ketones. I. Oxygen-17 and proton spectra and equilibrium constants. J. Am. Chem. Soc. 1967, 89, 749756,  DOI: 10.1021/ja00980a004
    21. 21
      Butler, T. C. The introduction of chloral hydrate into medical practice. Bull. Hist. Med. 1970, 44, 168172
    22. 22
      (a) West, R. Siegfried Ruhemann and the discovery of ninhydrin. J. Chem. Educ. 1965, 42, 386388,  DOI: 10.1021/ed042p386 .
      (b) Odén, S.; von Hofsten, B. Detection of fingerprints by the ninhydrin reaction. Nature 1954, 173, 449450,  DOI: 10.1038/173449a0
    23. 23
      Simmons, H. E.; Wiley, D. W. Fluoroketones. J. Am. Chem. Soc. 1960, 82, 22882296,  DOI: 10.1021/ja01494a047
    24. 24
      Bagnall, R. D.; Bell, W.; Pearson, K. New inhalation anaesthetics: I. Fluorinated 1,3-dioxolane derivatives. J. Fluorine Chem. 1977, 9, 359375,  DOI: 10.1016/S0022-1139(00)82169-7
    25. 25
      Brown, H. C.; Okamoto, Y. Substituent constants for aromatic substitution. J. Am. Chem. Soc. 1957, 79, 19131917,  DOI: 10.1021/ja01565a039
    26. 26
      Lowe, D. In The Pipeline. https://blogs.sciencemag.org/pipeline/archives/2015/11/05/another-funny-looking-structure-comes-through (accessed March 12, 2021).
    27. 27
      ClinCalc DrugStats Database. https://clincalc.com/DrugsStats/Top300Drugs.aspx (accessed April 6, 2021).
    28. 28
      Maryanoff, B. E.; Costanzo, M. J.; Nortey, S. O.; Greco, M. N.; Shank, R. P.; Schupsky, J. J.; Ortegon, M. P.; Vaught, J. L. Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives. J. Med. Chem. 1998, 41, 13151343,  DOI: 10.1021/jm970790w
    29. 29
      Rankovic, Z. CNS drug design: balancing physicochemical properties for optimal brain exposure. J. Med. Chem. 2015, 58, 25842608,  DOI: 10.1021/jm501535r
    30. 30
      Brand, S.; Norcross, N. R.; Thompson, S.; Harrison, J. R.; Smith, V. C.; Robinson, D. A.; Torrie, L. S.; McElroy, S. P.; Hallyburton, I.; Norval, S.; Scullion, P.; Stojanovski, L.; Simeons, F. R.; Aalten, D. V.; Frearson, J. A.; Brenk, R.; Fairlamb, A. H.; Ferguson, M. A.; Wyatt, P. G.; Gilbert, I. H.; Read, K. D. Lead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-!myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis. J. Med. Chem. 2014, 57, 98559869,  DOI: 10.1021/jm500809c
    31. 31
      Christensen, J.; Højskov, C. S.; Dam, M.; Poulsen, J. H. Plasma concentration of topiramate correlates with cerebrospinal fluid concentration. Ther. Drug Monit. 2001, 23, 529535,  DOI: 10.1097/00007691-200110000-00006
    32. 32
      Caldwell, G. W.; Wu, W. N.; Masucci, J. A.; McKown, L. A.; Gauthier, D.; Jones, W. J.; Leo, G. C.; Maryanoff, B. E. Metabolism and excretion of the antiepileptic/antimigraine drug, topiramate in animals and humans. Eur. J. Drug Metab. Pharmacokinet. 2005, 30, 151164,  DOI: 10.1007/BF03190614
    33. 33
      Patsalos, P. N. The mechanism of action of topiramate. Rev. Contemp. Pharmacother. 1999, 10, 147153
    34. 34
      (a) Monteiro, J.; Alves, M. G.; Oliveira, P. F.; Silva, B. M. Pharmacological potential of methylxanthines: Retrospective analysis and future expectations. Crit. Rev. Food Sci. Nutr. 2019, 59, 25972625,  DOI: 10.1080/10408398.2018.1461607 .
      (b) Matera, M. G.; Page, C. P.; Calzetta, L.; Rogliani, P.; Cazzola, M. Pharmacology and therapeutics of bronchodilators revisited. Pharmacol. Rev. 2020, 72, 218252,  DOI: 10.1124/pr.119.018150
    35. 35
      (a) Shukla, D.; Chakraborty, S.; Singh, S.; Mishra, B. Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. Expert Opin. Pharmacother. 2009, 10, 23432356,  DOI: 10.1517/14656560903200667 .
      (b) Matera, M. G.; Page, C.; Cazzola, M. Doxofylline is not just another theophylline!. Int. J. Chronic Obstruct. Pulm. Dis. 2017, 12, 34873493,  DOI: 10.2147/COPD.S150887
    36. 36
      (a) Zhao, X.; Ma, H.; Pan, Q.; Wang, H.; Qian, X.; Song, P.; Zou, L.; Mao, M.; Xia, S.; Ge, G.; Yang, L. Theophylline acetaldehyde as the initial product in doxophylline metabolism in human liver. Drug Metab. Dispos. 2020, 48, 345352,  DOI: 10.1124/dmd.119.089565 .
      (b) Grosa, G.; Franzone, J. S.; Biglino, G. Metabolism of doxophylline by rat liver microsomes. Drug Metab. Dispos. 1986, 14, 267270
    37. 37
      Griebel, G.; Stemmelin, J.; Lopez-Grancha, M.; Fauchey, V.; Slowinski, F.; Pichat, P.; Dargazanli, G.; Abouabdellah, A.; Cohen, C.; Bergis, O. E. The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents. Sci. Rep. 2018, 8, 2416,  DOI: 10.1038/s41598-018-20895-z
    38. 38
      Garde, D. J&J halts a depression program in the shadow of a fatal French trial. https://www.fiercebiotech.com/r-d/j-j-halts-a-depression-program-shadow-of-a-fatal-french-trial (accessed March 17, 2021).
    39. 39
      Belema, M.; Meanwell, N. A. Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect. J. Med. Chem. 2014, 57, 50575071,  DOI: 10.1021/jm500335h
    40. 40
      (a) Kazmierski, W. W.; Maynard, A.; Duan, M.; Baskaran, S.; Botyanszki, J.; Crosby, R.; Dickerson, S.; Tallant, M.; Grimes, R.; Hamatake, R.; Leivers, M.; Roberts, C. D.; Walker, J. Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound. J. Med. Chem. 2014, 57, 20582073,  DOI: 10.1021/jm4013104 .
      (b) Wilfret, D. A.; Walker, J.; Adkison, K. K.; Jones, L. A.; Lou, Y.; Gan, J.; Castellino, S.; Moseley, C. L.; Horton, J.; de Serres, M.; Culp, A.; Goljer, I.; Spreen, W. Safety, tolerability, pharmacokinetics, and antiviral activity of GSK2336805, an inhibitor of hepatitis C virus (HCV) NS5A, in healthy subjects and subjects chronically infected with HCV genotype 1. Antimicrob. Agents Chemother. 2013, 57, 50375044,  DOI: 10.1128/AAC.00910-13
    41. 41
      Tai, V. W.; Garrido, D.; Price, D. J.; Maynard, A.; Pouliot, J. J.; Xiong, Z.; Seal III, J. W.; Creech, K. L.; Kryn, L. H.; Baughman, T. M.; Peat, A. J. Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein. Bioorg. Med. Chem. Lett. 2014, 24, 22882294,  DOI: 10.1016/j.bmcl.2014.03.080
    42. 42
      (a) Chen, K. X.; Njoroge, G.; Arasappan, A.; Venkatraman, S.; Vibulbhan, B.; Yang, W.; Parekh, T. N.; Pichardo, J.; Prongay, A.; Cheng, K.; Butkiewicz, N.; Yao, N.; Madison, V.; Girijavallabhan, V. Novel potent hepatitis C virus NS3 serine protease inhibitors derived from proline-based macrocycles. J. Med. Chem. 2006, 49, 9951005,  DOI: 10.1021/jm050820s .
      (b) Chen, K. X.; Njoroge, F. G.; Vibulbhan, B.; Prongay, A.; Pichardo, J.; Madison, V.; Buevich, A.; Chan, T. M. Proline-based macrocyclic inhibitors of the hepatitis C virus: stereoselective synthesis and biological activity. Angew. Chem., Int. Ed. 2005, 44, 70247028,  DOI: 10.1002/anie.200501553
    43. 43
      (a) Sanglier, J.-J.; Quesniaux, V.; Fehr, T.; Hofmann, H.; Mahnke, M.; Memmert, K.; Schuler, W.; Zenke, G.; Gschwind, L.; Maurer, C.; Schilling, W. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92–308110: I. Taxonomy, fermentation, isolation and biological activity. J. Antibiot. 1999, 52, 466473,  DOI: 10.7164/antibiotics.52.466 .
      (b) Fehr, T.; Kallen, J.; Oberer, L.; Sanglier, J.-J.; Schilling, W. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92–308110: II. Structure elucidation, stereochemistry and physico-chemical properties. J. Antibiot. 1999, 52, 474479,  DOI: 10.7164/antibiotics.52.474
    44. 44
      Mackman, R.; Steadman, V. A.; Dean, D. K.; Jansa, P.; Poullennec, K. G.; Appleby, T.; Austin, C.; Blakemore, C. A.; Cai, R.; Cannizzaro, C.; Chin, G.; Chiva, J. C.; Dunbar, N. A.; Fliri, H.; Highton, A. J.; Hui, H.; Ji, M.; Jin, H.; Karki, K.; Keats, A. J.; Lazarides, L.; Lee, Y.; Liclican, A.; Mish, M.; Murray, B.; Pettit, S. B.; Yun, P.; Sangi, M.; Santos, R.; Sanvoisin, J.; Schmitz, U.; Schrier, A.; Siegel, D.; Sperandio, D.; Stepan, G.; Tian, Y.; Watt, G. M.; Yang, H.; Schultz, B. E. Discovery of a potent and orally bioavailable cyclophilin inhibitor derived from the sanglifehrin macrocycle. J. Med. Chem. 2018, 61, 94739499,  DOI: 10.1021/acs.jmedchem.8b00802
    45. 45
      Ma, X.; Idle, J. R.; Gonzalez, F. J. The pregnane X receptor: from bench to bedside. Expert Opin. Drug Metab. Toxicol. 2008, 4, 895908,  DOI: 10.1517/17425255.4.7.895
    46. 46
      Wang, Y.; Zhao, H.; Brewer, J. T.; Li, H.; Lao, Y.; Amberg, W.; Behl, B.; Akritopoulou-Zanze, I.; Dietrich, J.; Lange, U. E.; Pohlki, F.; Hoft, C.; Hornberger, W.; Djuric, S. W.; Sydor, J.; Mezler, M.; Relo, A. L.; Vasudevan, A. De novo design, synthesis, and biological evaluation of 3,4-disubstituted pyrrolidine sulfonamides as potent and selective glycine transporter 1 competitive inhibitors. J. Med. Chem. 2018, 61, 74867502,  DOI: 10.1021/acs.jmedchem.8b00295
    47. 47
      (a) Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 2009, 52, 67526756,  DOI: 10.1021/jm901241e .
      (b) Hirata, K.; Kotoku, M.; Seki, N.; Maeba, T.; Maeda, K.; Hirashima, S.; Sakai, T.; Obika, S.; Hori, A.; Hase, Y.; Yamaguchi, T.; Katsuda, Y.; Hata, T.; Miyagawa, N.; Arita, K.; Nomura, Y.; Asahina, K.; Aratsu, Y.; Kamada, M.; Adachi, T.; Noguchi, M.; Doi, S.; Crowe, P.; Bradley, E.; Steensma, R.; Tao, H.; Fenn, M.; Babine, R.; Li, X.; Thacher, S.; Hashimoto, H.; Shiozaki, M. SAR Exploration guided by LE and Fsp3: discovery of a selective and orally efficacious RORδ inhibitor. ACS Med. Chem. Lett. 2016, 7, 2327,  DOI: 10.1021/acsmedchemlett.5b00253
    48. 48
      Stojanovic-Radic, Z.; Pejic, M.; Dimitrijevic, M.; Aleksic, A.; Kumar, N. V.; Salehi, B.; Cho, W. C.; Sharifi-Rad, J. Piperine - a major principle of black pepper: a review of its bioactivity and studies. Appl. Sci. 2019, 9, 4270,  DOI: 10.3390/app9204270
    49. 49
      (a) Bertelsen, K. M.; Venkatakrishnan, K.; von Moltke, L. L.; Obach, R. S.; Greenblatt, D. J. Apparent mechanism-based inhibition of human CYP 2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab. Dispos. 2003, 31, 289293,  DOI: 10.1124/dmd.31.3.289 .
      (b) Kamel, E. M.; Lamsabhi, A. M. The quasi-irreversible inactivation of Cytochrome P450 enzymes by paroxetine: A computational approach. Org. Biomol. Chem. 2020, 18, 33343345,  DOI: 10.1039/D0OB00529K .
      (c) Zhao, S. X.; Dalvie, D. K.; Kelly, J. M.; Soglia, J. R.; Frederick, K. S.; Smith, E. B.; Obach, R. S.; Kalgutkar, A. S. NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. Chem. Res. Toxicol. 2007, 20, 16491657,  DOI: 10.1021/tx700132x
    50. 50
      (a) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A.-C.; Coste, H.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. The discovery of tadalafil: a novel and highly selective PDE5 Inhibitor. 1:5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues. J. Med. Chem. 2003, 46, 45254532,  DOI: 10.1021/jm030056e .
      (b) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A. C.; Coste, H.; Linget, J. M.; Kirilovsky, J.; Hyafil, F.; Labaudinière, R. The discovery of tadalafil: a novel and highly selective PDE5 Inhibitor. 2:2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione analogues. J. Med. Chem. 2003, 46, 45334542,  DOI: 10.1021/jm0300577 .
      (c) Curran, M. P.; Keating, G. M. Tadalafil. Drugs 2003, 63, 22032212,  DOI: 10.2165/00003495-200363200-00004
    51. 51
      Hartmann, J. T.; Lipp, H.-P. Camptothecin and podophyllotoxin derivatives inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profile. Drug Saf. 2006, 29, 209230,  DOI: 10.2165/00002018-200629030-00005
    52. 52
      Murray, M. Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Curr. Drug Metab. 2000, 1, 6784,  DOI: 10.2174/1389200003339270
    53. 53
      Bardin, E.; Pastor, A.; Semeraro, M.; Golec, A.; Hayes, K.; Chevalier, B.; Berhal, F.; Prestat, G.; Hinzpeter, A.; Gravier-Pelletier, C.; Pranke, I.; Sermet-Gaudelus, I. Modulators of CFTR. Updates on clinical development and future directions. Eur. J. Med. Chem. 2021, 213, 113195,  DOI: 10.1016/j.ejmech.2021.113195
    54. 54
      Keith, J. M.; Jones, W. M.; Tichenor, M.; Liu, J.; Seierstad, M.; Palmer, J. A.; Webb, M.; Karbarz, M.; Scott, B. P.; Wilson, S. J.; Luo, L.; Wennerholm, M. L.; Chang, L.; Rizzolio, M.; Rynberg, R.; Chaplan, S. R.; Breitenbucher, J. G. Preclinical characterization of the FAAH inhibitor JNJ-42165279. ACS Med. Chem. Lett. 2015, 6, 12041208,  DOI: 10.1021/acsmedchemlett.5b00353
    55. 55
      Rose, W. C.; Marathe, P. H.; Jang, G. R.; Monticello, T. M.; Balasubramanian, B. N.; Long, B.; Fairchild, C. R.; Wall, M. E.; Wani, M. C. Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization. Cancer Chemother. Pharmacol. 2006, 58, 7385,  DOI: 10.1007/s00280-005-0128-y
    56. 56
      Alig, L.; Alsenz, J.; Andjelkovic, M.; Bendels, S.; Bénardeau, A.; Bleicher, K.; Bourson, A.; David-Pierson, P.; Guba, W.; Hildbrand, S.; Kube, D.; Lübbers, T.; Mayweg, A. V.; Narquizian, R.; Neidhart, W.; Nettekoven, M.; Plancher, J.; Rocha, C.; Rogers-Evans, M.; Röver, S.; Schneider, G.; Taylor, S.; Waldmeier, P. Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity. J. Med. Chem. 2008, 51, 21152127,  DOI: 10.1021/jm701487t
    57. 57
      (a) Boyle, C. D.; Chackalamannil, S.; Chen, L.; Dugar, S.; Pushpavanam, P.; Billard, W.; Binch, H.; Crosby, H.; Cohen-Williams, M.; Coffin, V. L.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E. Benzylidene ketal derivatives as M2 muscarinic receptor antagonists. Bioorg. Med. Chem. Lett. 2000, 10, 27272730,  DOI: 10.1016/S0960-894X(00)00553-9 .
      (b) Boyle, C. D.; Chackalamannil, S.; Clader, J. W.; Greenlee, W. J.; Josien, H. B.; Kaminski, J. J.; Kozlowski, J. A.; McCombie, S. W.; Nazareno, D. V.; Tagat, J. R.; Wang, Y.; Zhou, G.; Billard, W.; Binch, H.; Crosby, G.; Cohen-Williams, M.; Coffin, V. L.; Cox, K. A.; Grotz, D. E.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E. Metabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitution. Bioorg. Med. Chem. Lett. 2001, 11, 23112314,  DOI: 10.1016/S0960-894X(01)00435-8
    58. 58
      (a) Franchini, S.; Sorbi, C.; Linciano, P.; Carnevale, G.; Tait, A.; Ronsisvalle, S.; Buccioni, M.; Del Bello, F.; Cilia, A.; Pirona, L.; Denora, N.; Iacobazzi, R. M.; Brasili, L. 1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity. Eur. J. Med. Chem. 2019, 176, 310325,  DOI: 10.1016/j.ejmech.2019.05.024 .
      (b) Linciano, P.; Sorbi, C.; Comitato, A.; Lesniak, A.; Bujalska-Zadrożny, M.; Pawłowska, A.; Bielenica, A.; Orzelska-Górka, J.; Kedzierska, E.; Biała, G.; Ronsisvalle, S.; Limoncella, S.; Casarini, L.; Cichero, E.; Fossa, P.; Satała, G.; Bojarski, A. J.; Brasili, L.; Bardoni, R.; Franchini, S. Identification of a potent and selective 5-HT1A receptor agonist with in vitro and in vivo antinociceptive activity. ACS Chem. Neurosci. 2020, 11, 41114127,  DOI: 10.1021/acschemneuro.0c00289
    59. 59
      (a) Dunn, M. I. A new antihypertensive drug. JAMA, J. Am. Med. Assoc. 1981, 245, 16391642,  DOI: 10.1001/jama.245.16.1639 .
      (b) Hengstmann, J. H.; Falkner, F. C. Disposition of guanethidine during chronic oral therapy. Eur. J. Clin. Pharmacol. 1979, 15, 121125,  DOI: 10.1007/BF00609875 .
      (c) Finnerty, F. A., Jr.; Brogden, R. N. Guanadrel, A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in hypertension. Drugs 1985, 30, 2231,  DOI: 10.2165/00003495-198530010-00003
    60. 60
      (a) Satoh, E.; Kasahara, R.; Fukatsu, K.; Aoki, T.; Harayama, H.; Murata, T. Benzpyrimoxan: design, synthesis, and biological activity of a novel insecticide. J. Pestic. Sci. 2021, 46, 109114,  DOI: 10.1584/jpestics.D20-069 .
      (b) Umetsu, N.; Shirai, Y. Development of novel pesticides in the 21st century. J. Pestic. Sci. 2020, 45, 5474,  DOI: 10.1584/jpestics.D20-201
    61. 61
      (a) McAtee, L. C.; Sutton, S. W.; Rudolph, D. A.; Li, X.; Aluisio, L. E.; Phuong, V. K.; Dvorak, C. A.; Lovenberg, T. W.; Carruthers, N. I.; Jones, T. K. Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX2R) antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 42254229,  DOI: 10.1016/j.bmcl.2004.06.032 .
      (b) Letavic, M. A.; Bonaventure, P.; Carruthers, N. I.; Dugovic, C.; Koudriakova, T.; Lord, B.; Lovenberg, T. W.; Ly, K. S.; Mani, N. S.; Nepomuceno, D.; Pippel, D. J.; Rizzolio, M.; Shelton, J. E.; Shah, C. R.; Shireman, B. T.; Young, L. K.; Yun, S. Novel octahydropyrrolo[3,4-c]pyrroles are selective orexin-2 antagonists: SAR leading to a clinical candidate. J. Med. Chem. 2015, 58, 56205636,  DOI: 10.1021/acs.jmedchem.5b00742
    62. 62
      (a) Trabocchi, A.; Menchi, G.; Guarna, F.; Machetti, F.; Scarpi, D.; Guarna, A. Design, synthesis, and applications of 3-aza-6,8-dioxabicyclo[3.2.1]octane-based scaffolds for peptidomimetic chemistry. Synlett 2006, 2006, 03310353,  DOI: 10.1055/s-2006-926249 .
      (b) Trabocchi, A.; Cini, N.; Menchi, G.; Guarna, A. A new bicyclic proline-mimetic amino acid. Tetrahedron Lett. 2003, 44, 34893492,  DOI: 10.1016/S0040-4039(03)00663-4 .
      (c) Trabocchi, A.; Menchi, G.; Danieli, E.; Guarna, A. Synthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostere. Amino Acids 2008, 35, 3744,  DOI: 10.1007/s00726-007-0636-7 .
      (d) Machetti, F.; Bucelli, I.; Indiani, G.; Guarna, A. Neat reaction of carboxylic acid methyl esters and amines for efficient parallel synthesis of scaffold amide libraries. C. R. Chim. 2003, 6, 631633,  DOI: 10.1016/S1631-0748(03)00097-3 .
      (e) Cini, N.; Danieli, E.; Menchi, G.; Trabocchi, A.; Bottoncetti, A.; Raspanti, S.; Pupi, A.; Guarna, A. 3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter. Bioorg. Med. Chem. 2006, 14, 51105120,  DOI: 10.1016/j.bmc.2006.04.019
    63. 63
      (a) Sherwood, J.; De bruyn, M.; Constantinou, A.; Moity, L.; McElroy, C. R.; Farmer, T. J.; Duncan, T.; Raverty, W.; Hunt, A. J.; Clark, J. H. Dihydrolevoglucosenone (Cyrene) as a bio-based alternative for dipolar aprotic solvents. Chem. Commun. 2014, 50, 96509652,  DOI: 10.1039/C4CC04133J .
      (b) Hughes, L.; McElroy, C. R.; Whitwood, A. C.; Hunt, A. J. Development of pharmaceutically relevant biobased intermediates though aldol condensation and Claisen-Schmidt reactions of dihydrolevoglucosenone (Cyrene®). Green Chem. 2018, 20, 44234427,  DOI: 10.1039/C8GC01227J .
      (c) Liu, X.; Carr, P.; Gardiner, M. G.; Banwell, M. G.; Elbanna, A. H.; Khalil, Z. G.; Capon, R. J. Levoglucosenone and its pseudoenantiomer iso-levoglucosenone as scaffolds for drug discovery and development. ACS Omega 2020, 5, 1392613939,  DOI: 10.1021/acsomega.0c01331
    64. 64
      (a) Sensi, P. History of the development of rifampin. Clin. Infect. Dis. 1983, 5, S402S406,  DOI: 10.1093/clinids/5.Supplement_3.S402 .
      (b) Wehrli, W.; Staehelin, M. Rifamycins and other ansamycins. Mechanism of Action of Antimicrobial and Antitumor Agents. Antibiotics. 1975, 3, 252268,  DOI: 10.1007/978-3-642-46304-4_16
    65. 65
      (a) Oppolzer, W.; Prelog, V.; Sensi, P. The composition of rifamycin B and related rifamycins. Experientia 1964, 20, 336339,  DOI: 10.1007/BF02171084 .
      (b) Leitich, J.; Oppolzer, W.; Prelog, V. On the configuration of rifamycin B and related rifamycins. Experientia 1964, 20, 343344,  DOI: 10.1007/BF02171086
    66. 66
      Bacchi, A.; Pelizzi, G.; Nebuloni, M.; Ferrari, P. Comprehensive study on structure-activity relationships of rifamycins: discussion of molecular and crystal structure and spectroscopic and thermochemical properties of rifamycin O. J. Med. Chem. 1998, 41, 23192332,  DOI: 10.1021/jm970791o
    67. 67
      Bergamini, N.; Fowst, G. Rifamycin SV. A review. Arzneim.-Forsch. 1965, 15 (Suppl), 9511002
    68. 68
      Rode, H. B.; Lade, D. M.; Grée, R.; Mainkar, P. S.; Chandrasekhar, S. Strategies towards the synthesis of anti-tuberculosis drugs. Org. Biomol. Chem. 2019, 17, 54285459,  DOI: 10.1039/C9OB00817A
    69. 69
      (a) Loos, U.; Musch, E.; Jensen, J. C.; Mikus, G.; Schwabe, H. K.; Eichelbaum, M. Pharmacokinetics of oral and intravenous rifampicin during chronic administration. Klin. Wochenschr. 1985, 63, 12051211,  DOI: 10.1007/BF01733779 .
      (b) Acocella, G. Clinical pharmacokinetics of rifampicin. Clin. Pharmacokinet. 1978, 3, 108127,  DOI: 10.2165/00003088-197803020-00002
    70. 70
      Campbell, E. A.; Korzheva, N.; Mustaev, A.; Murakami, K.; Nair, S.; Goldfarb, A.; Darst, S. A. Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell 2001, 104, 901912,  DOI: 10.1016/S0092-8674(01)00286-0
    71. 71
      Brogden, R. N.; Fitton, A. Rifabutin. Drugs 1994, 47, 9831009,  DOI: 10.2165/00003495-199447060-00008
    72. 72
      (a) Skinner, M. H.; Blaschke, T. F. Clinical pharmacokinetics of rifabutin. Clin. Pharmacokinet. 1995, 28, 115125,  DOI: 10.2165/00003088-199528020-00003 .
      (b) Blaschke, T. F.; Skinner, M. H. The clinical pharmacokinetics of rifabutin. Clin. Infect. Dis. 1996, 22, S15S22,  DOI: 10.1093/clinids/22.Supplement_1.S15
    73. 73
      Stahelin, H. F.; von Wartburg, A. The chemical and biological route from podophyllotoxin glucoside to etoposide: ninth Cain Memorial Award Lecture. Cancer Res. 1991, 51, 515
    74. 74
      (a) Joel, S. P.; Clark, P. I.; Heap, L.; Webster, L.; Robbins, S.; Craft, H.; Slevin, M. L. Pharmacological attempts to improve the bioavailability of oral etoposide. Cancer Chemother. Pharmacol. 1995, 37, 125133,  DOI: 10.1007/BF00685639 .
      (b) Shah, J. C.; Chen, J. R.; Chow, D. Preformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposide. Pharm. Res. 1989, 6, 408412,  DOI: 10.1023/A:1015935532725 .
      (c) Toffoli, G.; Corona, G.; Basso, B.; Boiocchi, M. Pharmacokinetic optimization of treatment with oral etoposide. Clin. Pharmacokinet. 2004, 43, 441466,  DOI: 10.2165/00003088-200443070-00002
    75. 75
      (a) Saulnier, M. G.; Langley, D.; Kadow, J. F.; Senter, P. D.; Knipe, J.; Tun, M. M.; Vyas, D. M.; Doyle, T. W. Synthesis of etoposide phosphate, BMY-40481, a water-soluble clinically active prodrug of etoposide. Bioorg. Med. Chem. Lett. 1994, 4, 25672572,  DOI: 10.1016/S0960-894X(01)80285-7 .
      (b) Chabot, G G; Armand, J P; Terret, C; de Forni, M; Abigerges, D; Winograd, B; Igwemezie, L; Schacter, L; Kaul, S; Ropers, J; Bonnay, M Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I study. J. Clin. Oncol. 1996, 14, 20202030,  DOI: 10.1200/JCO.1996.14.7.2020
    76. 76
      (a) Heimbach, T.; Oh, D.-M.; Li, L. Y; Rodrıguez-Hornedo, N.ır; Garcia, G.; Fleisher, D. Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs. Int. J. Pharm. 2003, 261, 8192,  DOI: 10.1016/S0378-5173(03)00287-4 .
      (b) Heimbach, T.; Oh, D. M.; Li, L. Y.; Forsberg, M.; Savolainen, J.; Leppänen, J.; Matsunaga, Y.; Flynn, G.; Fleisher, D. Absorption rate limit considerations for oral phosphate prodrugs. Pharm. Res. 2003, 20, 848856,  DOI: 10.1023/A:1023827017224
    77. 77
      Long, B. H. Mechanisms of action of teniposide (VM-26) and comparison with etoposide (VP-16). Semin. Oncol. 1992, 19 (Suppl. 6), 319
    78. 78
      (a) Splinter, T. A.; Holthuis, J. J.; Kok, T. C.; Post, M. H. Absolute bioavailability and pharmacokinetics of oral teniposide. Semin. Oncol. 1992, 19 (Suppl. 6), 2834.
      (b) Relling, M. V.; Evans, R.; Dass, C.; Desiderio, D. M.; Nemec, J. Human cytochrome P450 metabolism of teniposide and etoposide. J. Pharmacol. Exp. Ther. 1992, 261, 491496
    79. 79
      Jacob, D. A.; Mercer, S. L.; Osheroff, N.; Deweese, J. E. Etoposide quinone is a redox-dependent topoisomerase II poison. Biochemistry 2011, 50, 56605667,  DOI: 10.1021/bi200438m
    80. 80
      Yang, J.; Bogni, A.; Schuetz, E. G.; Ratain, M.; Dolan, M. E.; McLeod, H.; Gong, L.; Thorn, C.; Relling, M. V.; Klein, T. E.; Altman, R. B. Etoposide pathway. Pharmacogenet. Genomics 2009, 19, 552553,  DOI: 10.1097/FPC.0b013e32832e0e7f
    81. 81
      Pui, C. H.; Ribeiro, R. C.; Hancock, M. L.; Rivera, G. K.; Evans, W.; Raimondi, S. C.; Head, D. R.; Behm, F. G.; Mahmoud, M. H.; Sandlund, J. T.; Crist, W. M. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N. Engl. J. Med. 1991, 325, 16821687,  DOI: 10.1056/NEJM199112123252402
    82. 82
      Ashton, M. J.; Lawrence, C.; Karlsson, J.; Stuttle, K. A.; Newton, C. G.; Vacher, B. Y.; Webber, S.; Withnall, M. J. Anti-inflammatory 17β-thioalkyl-16α,17α-ketal and -acetal androstanes: a new class of airway selective steroids for the treatment of asthma. J. Med. Chem. 1996, 39, 48884896,  DOI: 10.1021/jm9604639
    83. 83
      (a) Gupta, R.; Jindal, D. P.; Kumar, G. Corticosteroids: the mainstay in asthma therapy. Bioorg. Med. Chem. 2004, 12, 63316342,  DOI: 10.1016/j.bmc.2004.05.045 .
      (b) Ye, Q.; He, X.; D’Urzo, A. A review on the safety and efficacy of inhaled corticosteroids in the management of asthma. Pulmon. Ther. 2017, 3, 118,  DOI: 10.1007/s41030-017-0043-5
    84. 84
      Edsbäcker, S.; Andersson, P.; Lindberg, C.; Ryrfeldt, A.; Thalén, A. Metabolic acetal splitting of budesonide. A novel inactivation pathway for topical glucocorticoids. Drug Metab. Dispos. 1987, 15, 412417
    85. 85
      Spencer, C. M.; McTavish, D. A review of its pharmacological properties and therapeutic efficacy in inflammatory bowel disease. Drugs 1995, 50, 854872,  DOI: 10.2165/00003495-199550050-00006
    86. 86
      de Weger, V. A.; Beijnen, J. H.; Schellens, J. H. M. Cellular and clinical pharmacology of the taxanes docetaxel and paclitaxel - a review. Anti-Cancer Drugs 2014, 25, 488494,  DOI: 10.1097/CAD.0000000000000093
    87. 87
      (a) Yassine, F.; Salibi, E.; Gali-Muhtasib, H. Overview of the formulations and analogues in the taxanes&. story. Curr. Med. Chem. 2016, 23, 45404558,  DOI: 10.2174/0929867323666160907124013 .
      (b) Yared, J. A.; Tkaczuk, K. H. R. Update on taxane development: new analogues and new formulations. Drug Des., Dev. Ther. 2012, 6, 371384,  DOI: 10.2147/DDDT.S28997 .
      (c) Baker, A. F.; Dorr, R. T. Drug interactions with the taxanes: clinical implications. Cancer Treat. Rev. 2001, 27, 221233,  DOI: 10.1053/ctrv.2001.0228
    88. 88
      (a) Ishiyama, T.; Iimura, S.; Ohsuki, S.; Uoto, K.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Bioorg. Med. Chem. Lett. 2002, 12, 10831086,  DOI: 10.1016/S0960-894X(02)00069-0 .
      (b) Ishiyama, T.; Iimura, S.; Yoshino, T.; Chiba, J.; Uoto, K.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 2. Bioorg. Med. Chem. Lett. 2002, 12, 28152819,  DOI: 10.1016/S0960-894X(02)00628-5 .
      (c) Takeda, Y.; Yoshino, T.; Uoto, K.; Chiba, J.; Ishiyama, T.; Iwahana, M.; Jimbo, T.; Tanaka, N.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 3. Bioorg. Med. Chem. Lett. 2003, 13, 185190,  DOI: 10.1016/S0960-894X(02)00891-0 .
      (d) Takeda, Y.; Uoto, K.; Iwahana, M.; Jimbo, T.; Nagata, M.; Atsumi, R.; Ono, C.; Tanaka, N.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 5. Bioorg. Med. Chem. Lett. 2004, 14, 32093215,  DOI: 10.1016/j.bmcl.2004.03.109 .
      (e) Takeda, Y.; Uoto, K.; Chiba, J.; Horiuchi, T.; Iwahana, M.; Atsumi, R.; Ono, C.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 4. Bioorg. Med. Chem. 2003, 11, 44314447,  DOI: 10.1016/S0968-0896(03)00454-1 .
      (f) Shionoya, M.; Jimbo, T.; Kitagawa, M.; Soga, T.; Tohgo, A. DJ-927, a novel oral taxane, overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivo. Cancer Sci. 2003, 94, 459466,  DOI: 10.1111/j.1349-7006.2003.tb01465.x .
      (g) Ono, C.; Takao, A.; Atsumi, R. Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys. Biol. Pharm. Bull. 2004, 27, 345351,  DOI: 10.1248/bpb.27.345 .
      (h) Roche, M.; Kyriakou, H.; Seiden, M. Drug evaluation: tesetaxel - an oral semisynthetic taxane derivative. Curr. Opin. Investig. Drugs 2006, 7, 10921099.
      (i) Baas, P.; Szczesna, A.; Albert, I.; Milanowski, J.; Juhasz, E.; Sztancsik, Z.; von Pawel, J.; Oyama, R.; Burgers, S. Phase I/II study of a 3 weekly oral taxane (DJ-927) in patients with recurrent, advanced non-small cell lung cancer. J. Thorac. Oncol. 2008, 3, 745750,  DOI: 10.1097/JTO.0b013e31817c73ff .
      (j) Al Idrus, A. Odonate abandons breast cancer chemo drug, closes its doors. https://www.fiercebiotech.com/biotech/odonate-abandons-breast-cancer-chemo-drug-closes-its-doors (accessed March 22, 2021).
    89. 89
      (a) Sakya, S. M.; Bertinato, P.; Pratt, B.; Suarez-Contreras, M.; Lundy, K. M.; Minich, M. L.; Cheng, H.; Ziegler, C. B.; Kamicker, B. J.; Hayashi, S. F.; Santoro, S. L.; George, D. W.; Bertsche, C. D. Azalide 3,6-ketals: antibacterial activity and structure-activity relationships of aryl and hetero aryl substituted analogues. Bioorg. Med. Chem. Lett. 2003, 13, 13731375,  DOI: 10.1016/S0960-894X(03)00100-8 .
      (b) Cheng, H.; Dirlam, J. P.; Ziegler, C. B.; Lundy, K. M.; Hayashi, S. F.; Kamicker, B. J.; Dutra, J. K.; Daniel, K. L.; Santoro, S. L.; George, D. M.; Bertsche, C. D.; Sakya, S. M.; Suarez-Contreras, M. Synthesis and SAR of azalide 3,6-ketal aromatic derivatives as potent Gram-positive and Gram-negative antibacterial agents. Bioorg. Med. Chem. Lett. 2002, 12, 24312434,  DOI: 10.1016/S0960-894X(02)00434-1
    90. 90
      Wu, Y.-J. Highlights of semi-synthetic developments from erythromycin A. Curr. Pharm. Des. 2000, 6, 181223,  DOI: 10.2174/1381612003401316
    91. 91
      (a) Luke, D. R.; Foulds, G. Disposition of oral azithromycin in humans. Clin. Pharmacol. Ther. 1997, 61, 641648,  DOI: 10.1016/S0009-9236(97)90098-9 .
      (b) Lode, H.; Borner, K.; Koeppe, P.; Schaberg, T. Azithromycin-review of key chemical, pharmacokinetic and microbiological features. J. Antimicrob. Chemother. 1996, 37, 18,  DOI: 10.1093/jac/37.suppl_C.1 .
      (c) Allin, D.; James, I.; Zachariah, J.; Carr, W.; Cullen, S.; Middleton, A.; Newson, P.; Lytle, T.; Coles, S. Comparison of once- and twice-daily clarithromycin in the treatment of adults with severe acute lower respiratory tract infections. Clin. Ther. 2001, 23, 19581968,  DOI: 10.1016/S0149-2918(01)80149-1
    92. 92
      Botelho, A. F. M.; Pierezan, F.; Soto-Blanco, B.; Melo, M. M. A review of cardiac glycosides: structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potential. Toxicon 2019, 158, 6368,  DOI: 10.1016/j.toxicon.2018.11.429
    93. 93
      (a) Cohen, A.; Kroon, R.; Schoemaker, H.; Breimer, D.; Vliet-Verbeek, A.; Brandenburg, H. The bioavailability of digoxin from three oral formulations measured by a specific HPLC assay. Br. J. Clin. Pharmacol. 1993, 35, 136142,  DOI: 10.1111/j.1365-2125.1993.tb05679.x .
      (b) Peters, U.; Falk, L. C.; Kalman, S. M. Digoxin metabolism in patients. Arch. Intern. Med. 1978, 138, 10741076,  DOI: 10.1001/archinte.1978.03630320018009
    94. 94
      (a) Cowie, M. R.; Fisher, M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat. Rev. Cardiol. 2020, 17, 761772,  DOI: 10.1038/s41569-020-0406-8 .
      (b) Moradi-Marjaneh, R.; Paseban, M.; Sahebkar, A. Natural products with SGLT2 inhibitory activity: possibilities of application for the treatment of diabetes. Phytother. Res. 2019, 33, 25182530,  DOI: 10.1002/ptr.6421 .
      (c) Mariadoss, A. V. A.; Vinyagam, R.; Rajamanickam, V.; Sankaran, V.; Venkatesan, S.; David, E. Pharmacological aspects and potential use of phloretin: a systemic review. Mini-Rev. Med. Chem. 2019, 19, 10601067,  DOI: 10.2174/1389557519666190311154425
    95. 95
      Tsujihara, K.; Hongu, M.; Saito, K.; Kawanishi, H.; Kuriyama, K.; Matsumoto, M.; Oku, A.; Ueta, K.; Tsuda, M.; Saito, A. Na+-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4′-dehydroxyphlorizin derivatives substituted on the B ring. J. Med. Chem. 1999, 42, 53115324,  DOI: 10.1021/jm990175n
    96. 96
      Kees, K. L.; Fitzgerald, J. J., Jr.; Steiner, K. E.; Mattes, J. F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and -pyrazolones. J. Med. Chem. 1996, 39, 39203928,  DOI: 10.1021/jm960444z
    97. 97
      (a) Washburn, W. N. Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2. J. Med. Chem. 2009, 52, 17851794,  DOI: 10.1021/jm8013019 .
      (b) Choi, C.-I. Sodium-glucose cotransporter 2 (SGLT2) inhibitors from natural products: discovery of next-generation antihyperglycemic agents. Molecules 2016, 21, 1136,  DOI: 10.3390/molecules21091136
    98. 98
      (a) Shimizu, K.; Fujikura, H.; Fushimi, N.; Nishimura, T.; Tatani, K.; Katsuno, K.; Fujimori, Y.; Watanabe, S.; Hiratochi, M.; Nakabayashi, T.; Kamada, N.; Arakawa, K.; Hikawa, H.; Azumaya, I.; Isaji, M. Discovery of remogliflozin etabonate: A potent and highly selective SGLT2 inhibitor. Bioorg. Med. Chem. 2021, 34, 116033,  DOI: 10.1016/j.bmc.2021.116033 .
      (b) Sigafoos, J. F.; Bowers, G. D.; Castellino, S.; Culp, A. G.; Wagner, D. S.; Reese, M. J.; Humphreys, J. E.; Hussey, E. K.; O’Connor Semmes, R. L.; Kapur, A.; Tao, W.; Dobbins, R. L.; Polli, J. Assessment of the drug interaction risk for remogliflozin etabonate, a sodium-dependent glucose cotransporter-2 inhibitor: evidence from in vitro, human mass balance, and ketoconazole interaction studies. Drug Metab. Dispos. 2012, 40, 20902101,  DOI: 10.1124/dmd.112.047258 .
      (c) Kapur, A.; O’Connor-Semmes, R.; Hussey, E. K.; Dobbins, R. L.; Tao, W.; Hompesch, M.; Smith, G. A.; Polli, J. W.; James, C. D. Jr.; Mikoshiba, I.; Nunez, D. J. First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus. BMC Pharmacol. Toxicol. 2013, 14, 26,  DOI: 10.1186/2050-6511-14-26
    99. 99
      (a) Mohan, V.; Mithal, A.; Joshi, S. R.; Aravind, S. R.; Chowdhury, S. Remogliflozin etabonate in the treatment of type 2 diabetes: design, development, and place in therapy. Drug Des., Dev. Ther. 2020, 14, 24872501,  DOI: 10.2147/DDDT.S221093 .
      (b) Markham, A. Remogliflozin etabonate: first global approval. Drugs 2019, 79, 11571161,  DOI: 10.1007/s40265-019-01150-9
    100. 100
      Ting, H. J.; Murad, J. P.; Espinosa, E. V. P.; Khasawneh, F. T. Thromboxane A2 receptor: biology and function of a peculiar receptor that remains resistant for therapeutic targeting. J. Cardiovasc. Pharmacol. Ther. 2012, 17, 248259,  DOI: 10.1177/1074248411424145
    101. 101
      (a) Fried, J.; John, V.; Szwedo, M. J., Jr.; Chen, C.; O’Yang, C.; Morinelli, T. A.; Okwu, A. K.; Halushka, P. V. Synthesis of 10,10-difluorothromboxane A2, a potent and chemically stable thromboxane agonist. J. Am. Chem. Soc. 1989, 111, 45104511,  DOI: 10.1021/ja00194a062 .
      (b) Morinelli, T. A.; Okwu, A. K.; Mais, D. E.; Halushka, P. V.; John, V.; Chen, C. K.; Fried, J. Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels. Proc. Natl. Acad. Sci. U. S. A. 1989, 86, 56005604,  DOI: 10.1073/pnas.86.14.5600 .
      (c) Jing, C.; Mallah, S.; Kriemen, E.; Bennett, S. H.; Fasano, V.; Lennox, A. J.; Hers, I.; Aggarwal, V. K. Synthesis, stability, and biological studies of fluorinated analogues of thromboxane A2. ACS Cent. Sci. 2020, 6, 9951000,  DOI: 10.1021/acscentsci.0c00310 .
      (d) Schaaf, T. R.; Bussolotti, D. L.; Parry, M. J.; Corey, E. J. Synthesis of 11a,9a-epoxymethanothromboxane A2: a stable, optically active TxA2 agonist. J. Am. Chem. Soc. 1981, 103, 65026505,  DOI: 10.1021/ja00411a044
    102. 102
      (a) Longridge, J. L.; Nicholson, S. The alkaline stability of (5Z)-7-([2RS,4RS,5SR]-4-o-hydroxyphenyl-2-trifluoromethyl-1,3-dioxan-5-yl)hept-5-enoic acid, ICI 185282. A remarkable intramolecular hydride transfer from a trifluoromethyl substituted carbon atom. J. Chem. Soc., Perkin Trans. 2 1990, 965970,  DOI: 10.1039/p29900000965 .
      (b) Brewster, A. G.; Brown, G. R.; Foubister, A. J.; Jessup, R.; Smithers, M. J. The synthesis of a novel thromboxane receptor antagonist 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl) hexenoic acid ICI 192605. Prostaglandins 1988, 36, 173178,  DOI: 10.1016/0090-6980(88)90304-8
    103. 103
      (a) O’Neill, P. M.; Posner, G. H. A medicinal chemistry perspective on artemisinin and related endoperoxides. J. Med. Chem. 2004, 47, 29452964,  DOI: 10.1021/jm030571c .
      (b) Krishna, S.; Bustamante, L.; Haynes, T. K.; Staines, H. M. Artemisinins: their growing importance in medicine. Trends Pharmacol. Sci. 2008, 29, 520527,  DOI: 10.1016/j.tips.2008.07.004
    104. 104
      (a) Ilett, K. F.; Ethell, B. T.; Maggs, J. L.; Davis, D. M. E.; Batty, K. T.; Burchell, B.; Binh, T. W.; Thu, L. T.; Hung, N. C.; Pirmohamed, M.; Park, B. K.; Edwards, G. Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab. Dispos. 2002, 30, 10051012,  DOI: 10.1124/dmd.30.9.1005 .
      (b) O’Neill, P. M.; Scheinmann, F.; Stachulski, A. V.; Maggs, J. L.; Park, B. K. Efficient preparations of the α-glucuronides of dihydroartemisinin and structural confirmation of the human glucuronide metabolite. J. Med. Chem. 2001, 44, 14671470,  DOI: 10.1021/jm001061a
    105. 105
      (a) Nga, T. T. T.; Menage, C.; Begue, J.-P.; Bonnet-Delpon, D.; Gantier, J.-C.; Pradines, B.; Doury, J.-C.; Thac, T. D. Synthesis and antimalarial activities of fluoroalkyl derivatives of dihydroartemisinin. J. Med. Chem. 1998, 41, 41014108,  DOI: 10.1021/jm9810147 .
      (b) Magueur, G.; Crousse, B.; Charneau, S.; Grellier, P.; Begue, J.-P.; Bonnet-Delpon, D. Fluoroartemisinin: trifluoromethyl analogues of artemether and artesunate. J. Med. Chem. 2004, 47, 26942699,  DOI: 10.1021/jm0310333 .
      (c) Bgu, J.-P.; Bonnet-Delpon, D. Antimalarial fluoroartimisinins: increased metabolic and chemical stability. Fluorine in Medicinal Chemistry and Chemical Biology 2009, 141163,  DOI: 10.1002/9781444312096.ch6 .
      (d) Njokah, M. J.; Kang’ethe, J. N.; Kinyua, J.; Kariuki, D.; Kimani, F. T. In vitro selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemisinin. Malar. J. 2016, 15, 381,  DOI: 10.1186/s12936-016-1443-y
    106. 106
      Elkeles, R. Fibrates: old drugs with a new role in type 2 diabetes prevention?. Br. J. Diabetes Vasc. Dis. 2011, 11, 49,  DOI: 10.1177/1474651410397245
    107. 107
      Pirat, C.; Farce, A.; Lebegue, N.; Renault, N.; Furman, C.; Millet, R.; Yous, S.; Speca, S.; Berthelot, P.; Desreumaux, P.; Chavatte, P. Targeting peroxisome proliferator-activated receptors (PPARs): development of modulators. J. Med. Chem. 2012, 55, 40274061,  DOI: 10.1021/jm101360s
    108. 108
      (a) Asaki, T.; Aoki, T.; Hamamoto, T.; Sugiyama, Y.; Ohmachi, S.; Kuwabara, K.; Murakami, K.; Todo, M. Structure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor δ. (PPARα) agonists. Bioorg. Med. Chem. 2008, 16, 981994,  DOI: 10.1016/j.bmc.2007.10.007 .
      (b) Aoki, T.; Asaki, T.; Hamamoto, T.; Sugiyama, Y.; Ohmachi, S.; Kuwabara, K.; Murakami, K.; Todo, M. Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor δ (PPARα) agonists. Bioorg. Med. Chem. Lett. 2008, 18, 21282132,  DOI: 10.1016/j.bmcl.2008.01.086
    109. 109
      (a) Tschierske, C.; Kshler, H.; Zaschke, H.; Kleinpete, E. The anomeric effect of the carboethoxy group in oxygen and sulfur containing heterocycles. Tetrahedron 1989, 45, 69876998,  DOI: 10.1016/S0040-4020(01)89165-1 .
      (b) Harabe, T.; Matsumoto, T.; Shioiri, T. Conformational analysis and selective hydrolysis of 2,5-disubstituted-1,3-dioxane-2-carboxylic acid esters. Tetrahedron Lett. 2007, 48, 14431446,  DOI: 10.1016/j.tetlet.2006.12.117 .
      (c) Harabe, T.; Matsumoto, T.; Shioiri, T. Esters of 2,5-multisubstituted-1,3-dioxane-2-carboxylic acid: their conformational analysis and selective hydrolysis. Tetrahedron 2009, 65, 40444052,  DOI: 10.1016/j.tet.2009.02.076
    110. 110
      (a) Zaware, P.; Shah, S. R.; Pingali, H.; Makadia, P.; Thube, B.; Pola, S.; Patel, D.; Priyadarshini, P.; Suthar, D.; Shah, M.; Jamili, J.; Sairam, K. V.; Giri, S.; Patel, L.; Patel, H.; Sudani, H.; Patel, H.; Jain, M.; Patel, P.; Bahekar, R. Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/δ dual agonist into a selective PPAR agonist through bioisosteric modification. Bioorg. Med. Chem. Lett. 2011, 21, 628632,  DOI: 10.1016/j.bmcl.2010.12.032 .
      (b) Pingali, H.; Jain, M.; Shah, S.; Patil, P.; Makadia, P.; Zaware, P.; Sairam, K. V.; Jamili, J.; Goel, A.; Patel, M.; Patel, P. Modulation of PPAR receptor subtype selectivity of the ligands: Aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety. Bioorg. Med. Chem. Lett. 2008, 18, 64716475,  DOI: 10.1016/j.bmcl.2008.10.062
    111. 111
      LeMahieu, R. A.; Carson, M.; Kierstead, R. W.; Fern, L. M.; Grunberg, E. Glycoside cleavage reactions on erythromycin A. Preparation of erythronolide A. J. Med. Chem. 1974, 17, 953956,  DOI: 10.1021/jm00255a009
    112. 112
      (a) Martin, R.; Plancq, B.; Gavelle, O.; Wagner, B.; Fischer, H.; Bendels, S.; Müller, K. Remote modulation of amine basicity by a phenylsulfone and a phenylthio group. ChemMedChem 2007, 2, 285287,  DOI: 10.1002/cmdc.200600265 .
      (b) Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 11001115,  DOI: 10.1002/cmdc.200700059
    113. 113
      Lenci, E.; Calugi, L.; Trabocchi, A. Occurrence of morpholine in central nervous system drug discovery. ACS Chem. Neurosci. 2021, 12, 378390,  DOI: 10.1021/acschemneuro.0c00729
    114. 114
      (a) Hale, J. L.; Mills, S. G.; MacCoss, M.; Shah, S. K.; Qi, H.; Mathre, D. J.; Cascieri, M. A.; Sadowski, S.; Strader, C. D.; MacIntyre, D. E.; Metzger, J. M. 2(S)-((3,5-Bis(trifluoromethyl)benzyl)-oxy)-3(S)-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine (1): a potent, orally active, morpholine-based human neurokinin-1 receptor antagonist. J. Med. Chem. 1996, 39, 17601762,  DOI: 10.1021/jm950654w .
      (b) Ladduwahetty, T.; Baker, R.; Cascieri, M. A.; Chambers, M. S.; Haworth, K.; Keown, L. E.; MacIntyre, D. E.; Metzger, J. M.; Owen, S.; Rycroft, W.; Sadowski, S.; Seward, E. M.; Shepheard, S. L.; Swain, C. J.; Tattersall, F. D.; Watt, A. P.; Williamson, D. W.; Hargreaves, R. J. N-Heteroaryl-2-phenyl-3-(benzyloxy)piperidines: a novel class of potent orally active human NK1 antagonists. J. Med. Chem. 1996, 39, 29072914,  DOI: 10.1021/jm9506534 .
      (c) Chen, S.; Lu, M.; Liu, D.; Yang, L.; Yi, C.; Ma, L.; Zhang, H.; Liu, Q.; Frimurer, T. M.; Wang, M.-W.; Schwartz, T. W.; Stevens, R. C.; Wu, B.; Wüthrich, K.; Zhao, Q. Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography. Nat. Commun. 2019, 10, 638,  DOI: 10.1038/s41467-019-08568-5 .
      (d) Gangula, S.; Elati, C. R.; Mudunuru, S. V.; Nardela, A.; Dongamanti, A.; Bhattacharya, A.; Bandichhor, R. Synthesis of all enantiomerically pure diastereomers of aprepitant. Synth. Commun. 2010, 40, 22542268,  DOI: 10.1080/00397910903221084
    115. 115
      Hale, J. J.; Mills, S. G.; MacCoss, M.; Dorn, C. P.; Finke, P. E.; Budhu, R. J.; Reamer, R. A.; Huskey, S. W.; Luffer-Atlas, D.; Dean, B. J.; McGowan, E. M.; Feeney, W. P.; Chiu, S. L.; Cascieri, M. A.; Chicchi, G. G.; Kurtz, M. M.; Sadowski, S.; Ber, E.; Tattersall, F. D.; Rupniak, N. M.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; Metzger, J. M.; MacIntyre, D. E. Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. J. Med. Chem. 2000, 43, 12341241,  DOI: 10.1021/jm990617v
    116. 116
      (a) Fuller, N. O.; Hubbs, J. J.; Austin, W. F.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M.; Tate, B.; Xia, W.; Ives, J. L.; Findeis, M. A.; Bronk, B. S. Initial optimization of a new series of γ-secretase modulators derived from a triterpene glycoside. ACS Med. Chem. Lett. 2012, 3, 908913,  DOI: 10.1021/ml300256p .
      (b) Hubbs, J. L.; Fuller, N. O.; Austin, W. F.; Shen, R.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M.; Tate, B.; Xia, W.; Ives, J.; Bronk, B. S. Optimization of a natural product-based class of γ-secretase modulators. J. Med. Chem. 2012, 55, 92709282,  DOI: 10.1021/jm300976b .
      (c) Loureiro, R. M.; Dumin, J. A.; McKee, T. D.; Austin, W. F.; Fuller, N. O.; Hubbs, J. L.; Shen, R.; Jonker, J.; Ives, J.; Bronk, B. S.; Tate, B. Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models. Alzheimer's Res. Ther. 2013, 5, 19,  DOI: 10.1186/alzrt173 .
      (d) Fuller, N. O.; Hubbs, J. L.; Austin, W. F.; Shen, R.; Ives, J.; Osswald, G.; Bronk, B. S. Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ-Secretase Modulator. Org. Process Res. Dev. 2014, 18, 683692,  DOI: 10.1021/op500072b
    117. 117
      (a) Kaneko, S.; Arai, M.; Uchida, T.; Harasaki, T.; Fukuoka, T.; Konosu, T. Synthesis and evaluation of N-substituted 1,4-oxazepanyl sordaricins as selective fungal EF-2 inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 17051708,  DOI: 10.1016/S0960-894X(02)00290-1 .
      (b) Arai, M.; Harasaki, T.; Fukuoka, T.; Kaneko, S.; Konosu, T. Synthesis and evaluation of novel pyrrolidinyl sordaricin derivatives as antifungal agents. Bioorg. Med. Chem. Lett. 2002, 12, 27332736,  DOI: 10.1016/S0960-894X(02)00534-6 .
      (c) Serrano-Wu, M. H.; St. Laurent, D. R.; Chen, Y.; Huang, S.; Lam, K.-R.; Matson, J. A.; Mazzucco, C. E.; Stickle, T. M.; Tully, T. P.; Wong, H. S.; Vyas, D. M.; Balasubramanian, B. N. Sordarin oxazepine derivatives as potent antifungal agents. Bioorg. Med. Chem. Lett. 2002, 12, 27572760,  DOI: 10.1016/S0960-894X(02)00529-2 .
      (d) Serrano-Wu, M. H.; Laurent, D. R.S..; Carroll, T. M.; Dodier, M.; Gao, Q.; Gill, P.; Quesnelle, C.; Marinier, A.; Mazzucco, C. E.; Regueiro-Ren, A.; Stickle, T. M.; Wu, D.; Yang, H.; Yang, Z.; Zheng, M.; Zoeckler, M. E.; Vyas, D. M.; Balasubramanian, B. N. Identification of a broad-spectrum azasordarin with improved pharmacokinetic properties. Bioorg. Med. Chem. Lett. 2003, 13, 14191423,  DOI: 10.1016/S0960-894X(03)00161-6 .
      (e) Kamai, Y.; Kakuta, M.; Shibayama, T.; Fukuoka, T.; Kuwahara, S. Antifungal activities of R-135853, a sordarin derivative, in experimental candidiasis in mice. Antimicrob. Agents Chemother. 2005, 49, 5256,  DOI: 10.1128/AAC.49.1.52-56.2005
    118. 118
      Bueno, A. B.; Agejas, J.; Broughton, H.; Dally, R.; Durham, T. B.; Espinosa, J. F.; Gonzalez, R.; Hahn, P. J.; Marcos, A.; Rodríguez, R.; Sanz, G.; Soriano, J. F.; Timm, D.; Vidal, P.; Yang, H.; McCarthy, J. R. Optimization of hydroxyethylamine transition state isosteres as aspartic protease inhibitors by exploiting conformational preferences. J. Med. Chem. 2017, 60, 98079820,  DOI: 10.1021/acs.jmedchem.7b01304
    119. 119
      (a) Eliel, E. I.; Alcudia, F. Acetylcholine analogues. Conformational equilibriums dominated by electrostatic interactions. J. Am. Chem. Soc. 1974, 96, 19391941,  DOI: 10.1021/ja00813a051 .
      (b) Kaloustian, M. K.; Dennis, N.; Mager, S.; Evans, S. A.; Alcudia, F.; Eliel, E. I. Conformational analysis. XXXI. Conformational equilibria of 1,3-dioxanes with polar substituents at C-5. J. Am. Chem. Soc. 1976, 98, 956965,  DOI: 10.1021/ja00420a015
    120. 120
      Pasternak, A.; Pan, Y.; Marino, D.; Sanderson, P. E.; Mosley, R.; Rohrer, S. P.; Birzin, E. T.; Huskey, S. W.; Jacks, T.; Schleim, K. D.; Cheng, K.; Schaeffer, J. M.; Patchett, A. A.; Yang, L. Potent, orally bioavailable somatostatin agonists: good absorption achieved by urea backbone cyclization. Bioorg. Bioorg. Med. Chem. Lett. 1999, 9, 491496,  DOI: 10.1016/S0960-894X(99)00016-5
    121. 121
      (a) Li, L.; Okumu, A.; Dellos-Nolan, S.; Li, Z.; Karmahapatra, S.; English, A.; Yalowich, J. C.; Wozniak, D. J.; Mitton-Fry, M. J. Synthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moiety. Bioorg. Med. Chem. Lett. 2018, 28, 24772480,  DOI: 10.1016/j.bmcl.2018.06.003 .
      (b) Lu, Y.; Papa, J. L.; Nolan, S.; English, A.; Seffernick, J. T.; Shkolnikov, N.; Powell, J.; Lindert, S.; Wozniak, D. J.; Yalowich, J.; Mitton-Fry, M. J. Dioxane-linked amide derivatives as novel bacterial topoisomerase inhibitors against Gram-positive Staphylococcus aureus. ACS Med. Chem. Lett. 2020, 11, 24462454,  DOI: 10.1021/acsmedchemlett.0c00428
    122. 122
      Kemp, J. A.; Keebaugh, A.; Edson, J. A.; Chow, D.; Kleinman, M. T.; Chew, Y. C.; McCracken, A. N.; Edinger, A. L.; Kwon, Y. J. Biocompatible chemotherapy for leukemia by acid-cleavable, PEGylated FTY720. Bioconjugate Chem. 2020, 31, 673684,  DOI: 10.1021/acs.bioconjchem.9b00822
    123. 123
      Kirby, A. J.; Percy, J. M. Intramolecular proton-transfer catalysis of nucleophilic catalysis of acetal hydrolysis. The hydrolysis of 8-dimethylamino-1-methoxymethoxynaphthalene. J. Chem. Soc., Perkin Trans. 2 1989, 907912,  DOI: 10.1039/p29890000907
    124. 124
      (a) Bi, L.; Zhao, M.; Gu, K.; Wang, C.; Ju, J.; Peng, S. Toward the development of chemoprevention agents (III): Synthesis and anti-inflammatory activities of a new class of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes. Bioorg. Med. Chem. 2008, 16, 17641774,  DOI: 10.1016/j.bmc.2007.11.017 .
      (b) Bi, L.; Zhang, Y.; Zhao, M.; Wang, C.; Chan, P.; Tok, J. B.-H.; Peng, S. Novel synthesis and anti-inflammatory activities of 2,5-disubstituted-dioxacycloalkanes. Bioorg. Med. Chem. 2005, 13, 56405646,  DOI: 10.1016/j.bmc.2005.05.032
    125. 125
      (a) Dovgan, I.; Kolodych, S.; Koniev, O.; Wagner, A. 2-(Maleimidomethyl)-1,3-dioxanes (MD): a serum-stable self-hydrolysable hydrophilic alternative to classical maleimide conjugation. Sci. Rep. 2016, 6, 30835,  DOI: 10.1038/srep30835 .
      (b) Tobaldi, E.; Dovgan, I.; Mosser, M.; Becht, J.-M.; Wagner, A. Structural investigation of cyclo-dioxo maleimide cross-linkers for acid and serum stability. Org. Biomol. Chem. 2017, 15, 93059310,  DOI: 10.1039/C7OB01757J
    126. 126
      Maertens, J. A. History of the development of azole derivatives. Clin. Microbiol. Infect. 2004, 10, 110,  DOI: 10.1111/j.1470-9465.2004.00841.x
    127. 127
      Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. Antimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent. J. Med. Chem. 1979, 22, 10031005,  DOI: 10.1021/jm00194a023
    128. 128
      (a) Vanden Bossche, H.; Heeres, J.; Backx, L. J. J.; Marichal, P.; Willemsens, G. Discovery, chemistry, mode of action, and selectivity of itraconazole. In Cutaneus Antifungal Agents; Rippon, J. W., Fromtling, R. A., Eds.; Marcel Decker Inc.: New York, 1993; pp 263283.
      (b) Martin, M. V. The use of fluconazole and itraconazole in the treatment of Candida albicans infections: a review. J. Antimicrob. Chemother. 1999, 44, 429437,  DOI: 10.1093/jac/44.4.429
    129. 129
      Fukami, T.; Iida, A.; Konishi, K.; Nakajima, M. Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicity. Biochem. Pharmacol. 2016, 116, 153161,  DOI: 10.1016/j.bcp.2016.07.007
    130. 130
      (a) Niwa, T.; Imagawa, Y.; Yamazaki, H. Drug interactions between nine antifungal agents and drugs metabolized by human cytochromes P450. Curr. Drug Metab. 2015, 15, 651679,  DOI: 10.2174/1389200215666141125121511 .
      (b) Khojasteh, S. C.; Prabhu, S.; Kenny, J. R.; Halladay, J. S.; Lu, A. Y. H. Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity. Eur. J. Drug Metab. Pharmacokinet. 2011, 36, 116,  DOI: 10.1007/s13318-011-0024-2
    131. 131
      (a) Van Tyle, J. H. Ketoconazole; Mechanism of action, spectrum of activity, pharmacokinetics, drug interactions, adverse reactions and therapeutic use. Pharmacotherapy 1984, 4, 343373,  DOI: 10.1002/j.1875-9114.1984.tb03398.x .
      (b) Rodriguez, R. J.; Acosta, D., Jr. Metabolism of ketoconazole and deacetylated ketoconazole by rat hepatic microsomes and flavin-containing monooxygenases. Drug Metab. Dispos. 1997, 25, 772777
    132. 132
      (a) Poirier, J. M.; Lebot, M.; Descamps, P.; Levy, M.; Cheymol, G. Determination of itraconazole and its active metabolite in plasma by column liquid chromatography. Ther. Drug Monit. 1994, 16, 596601,  DOI: 10.1097/00007691-199412000-00011 .
      (b) Peng, C. C.; Shi, W.; Lutz, J. D.; Kunze, K. L.; Liu, J. O.; Nelson, W. L.; Isoherranen, N. Stereospecific metabolism of itraconazole by CYP3A4: dioxolane ring scission of azole antifungals. Drug Metab. Dispos. 2012, 40, 426435,  DOI: 10.1124/dmd.111.042739
    133. 133
      (a) Sawyer, P. R.; Brogden, R. N.; Pinder, R. M.; Speight, T. M.; Avery, G. S. Miconazole: review of its antifungal activity and therapeutic efficacy. Drugs 1975, 9, 406423,  DOI: 10.2165/00003495-197509060-00002 .
      (b) Fothergill, A. W. Miconazole: a historical perspective. Expert Rev. Anti-Infect. Ther. 2006, 4, 171175,  DOI: 10.1586/14787210.4.2.171
    134. 134
      Godefroi, E. F.; Heeres, J.; Van Cutsem, J.; Janssen, P. A. J. The preparation and antimycotic properties of derivatives of 1-phenethylimidazole. J. Med. Chem. 1969, 12, 784791,  DOI: 10.1021/jm00305a014
    135. 135
      Heeres, J.; Van Cutsem, J. Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles. J. Med. Chem. 1981, 24, 13601364,  DOI: 10.1021/jm00143a019
    136. 136
      Heeres, J.; Meerpoel, L.; Lewi, P. Conazoles. Molecules 2010, 15, 41294188,  DOI: 10.3390/molecules15064129
    137. 137
      Lewis, D. F.; Wiseman, A.; Tarbit, M. H. Molecular modelling of lanosterol 14α-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform: quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivatives. J. Enzyme Inhib. 1999, 14, 175192,  DOI: 10.3109/14756369909030315
    138. 138
      (a) Collis, A. J.; Foster, M. L.; Halley, F.; Maslen, C.; McLay, I. M.; Page, K. M.; Redford, E. J.; Souness, J. E.; Wilsher, N. E. RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency. Bioorg. Med. Chem. Lett. 2001, 11, 693696,  DOI: 10.1016/S0960-894X(01)00034-8 .
      (b) McKenna, J. M.; Halley, F.; Souness, J. E.; McLay, I. M.; Pickett, S. D.; Collis, A. J.; Page, K.; Ahmed, I. An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors. J. Med. Chem. 2002, 45, 21732184,  DOI: 10.1021/jm011132l
    139. 139
      (a) Abbotto, A.; Bradamante, S.; Pagani, G. A. Diheteroarylmethanes. 5.1 E-Z isomerism of carbanions substituted by 1,3-azoles: 13C and 15N δ-charge/shift relationships as source for mapping charge and ranking the electron-withdrawing power of heterocycles. J. Org. Chem. 1996, 61, 17611769,  DOI: 10.1021/jo951884l .
      (b) Abbotto, A.; Bradamante, S.; Facchetti, A.; Pagani, G. A. Metal chelation aptitudes of bis(o-azaheteroaryl)methanes as tuned by heterocycle charge demands. J. Org. Chem. 2002, 67, 57535772,  DOI: 10.1021/jo025696o
    140. 140
      Collis, A.; Halley, F.; McClay, I. Heteroaryl-cyclic acetals. U.S. Patent 7,479,501 B2. January 30th, 2009.
    141. 141
      (a) Lovering, F. Escape from flatland 2: complexity and promiscuity. MedChemComm 2013, 4, 515519,  DOI: 10.1039/c2md20347b .
      (b) Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson, J. A.; Shamji, A. F.; Wagner, B. K.; Koehler, A. N.; Schreiber, S. L. Small molecules of different synthetic and natural origins have distinct distributions of structural complexity that correlate with protein binding profiles. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 1878718792,  DOI: 10.1073/pnas.1012741107 .
      (c) Meanwell, N. A. Improving drug design: an update on recent applications of efficiency metrics, strategies for replacing problematic elements, and compounds in nontraditional drug space. Chem. Res. Toxicol. 2016, 29, 564616,  DOI: 10.1021/acs.chemrestox.6b00043
    142. 142
      Astles, P. C.; Ashton, M. J.; Bridge, A. W.; Harris, N. V.; Hart, T. W.; Parrott, D. P.; Porter, B.; Riddell, D.; Smith, C.; Williams, R. J. Acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT. J. Med. Chem. 1996, 39, 14231432,  DOI: 10.1021/jm9505876
    143. 143
      (a) Dostertp, P.; Langlois, M.; Guerret, P.; Ancher, J. F.; Bucher, B.; Mocquet, G. Synthesis and pharmacological properties of analogues of oxapadol, a new analgesic agent. Eur. J. Med. Chem. 1980, 15, 199205.
      (b) Mocquet, G.; Coston, A.; Jalfre, M. Animal pharmacology of oxapadol (MD 720111), a new non-narcotic analgesic. Experientia 1980, 36, 9697,  DOI: 10.1007/BF02003996
    144. 144
      (a) Boureau, F.; Laquais, B.; Vadrot, M.; Willer, J.-C. Human neuropharmacological findings with oxapadol (MD 720111), a new non-narcotic analgesic. Experientia 1980, 36, 9798,  DOI: 10.1007/BF02003997 .
      (b) Ancher, J. F.; Donath, A.; Malnoe, A.; Morizur, J. P.; Strolin Bekedetti, M. Urinary metabolites of oxapadol (MD720111), a new non-narcotic analgesic agent, in the rat, dog and man. Xenobiotica 1981, 11, 519530,  DOI: 10.3109/00498258109045863
    145. 145
      Lenci, E.; Menchi, G.; Saldívar-Gonzalez, F.; Medina-Franco, J. L.; Trabocchi, A. Bicyclic acetals: biological relevance, scaffold analysis, and applications in diversity-oriented synthesis. Org. Biomol. Chem. 2019, 17, 10371052,  DOI: 10.1039/C8OB02808G
    146. 146
      (a) Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi, E.; Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.; Kimata, H.; Nakayama, K.; Tsuda-Tsukimoto, M. Discovery of canagliflozin, a novel c-glucoside with thiophene ring, as sodium-dependent glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J. Med. Chem. 2010, 53, 63556360,  DOI: 10.1021/jm100332n .
      (b) Lamos, E. M.; Younk, L. M.; Davis, S. N. Canagliflozin, an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin. Drug Metab. Toxicol. 2013, 9, 763775,  DOI: 10.1517/17425255.2013.791282
    147. 147
      (a) Meng, W.; Ellsworth, B. A.; Nirschl, A. A.; McCann, P. J.; Patel, M.; Girotra, R. N.; Wu, G.; Sher, P. M.; Morrison, E. P.; Biller, S. A.; Zahler, R. A.; Deshpande, P. P.; Pullockaran, A.; Hagan, D. L.; Morgan, N.; Taylor, J. R.; Obermeier, M. T.; Humphreys, W. G.; Khanna, A.; Discenza, L.; Robertson, J. G.; Wang, A.; Han, S.; Wetterau, J. R.; Janovitz, E. B.; Flint, O. P.; Whaley, J. M.; Washburn, W. N. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2008, 51, 11451149,  DOI: 10.1021/jm701272q .
      (b) Plosker, G. L. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs 2012, 72, 22892312,  DOI: 10.2165/11209910-000000000-00000
    148. 148
      Haider, K.; Pathak, A.; Rohilla, A.; Haider, M. R.; Ahmad, K.; Yar, M. S. Synthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: a review. Eur. J. Med. Chem. 2019, 184, 111773,  DOI: 10.1016/j.ejmech.2019.111773
    149. 149
      (a) Mascitti, V.; Maurer, T. S.; Robinson, R. P.; Bian, J.; Boustany-Kari, C. M.; Brandt, T.; Collman, B. M.; Kalgutkar, A. S.; Klenotic, M. K.; Leininger, M. T.; Lowe, A.; Maguire, R. J.; Masterson, V. M.; Miao, Z.; Mukaiyama, E.; Patel, J. D.; Pettersen, J. C.; Preville, C.; Samas, B.; She, L.; Sobol, Z.; Steppan, C. M.; Stevens, B. D.; Thuma, B. A.; Tugnait, M.; Zeng, D.; Zhu, T. Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors. J. Med. Chem. 2011, 54, 29522960,  DOI: 10.1021/jm200049r .
      (b) Mascitti, V.; Thuma, B. A.; Smith, A. C.; Robinson, R. P.; Brandt, T.; Kalgutkar, A. S.; Maurer, T. S.; Samas, B.; Sharma, R. On the importance of synthetic organic chemistry in drug discovery: reflections on the discovery of antidiabetic agent ertugliflozin. MedChemComm 2013, 4, 101111,  DOI: 10.1039/C2MD20163A
    150. 150
      (a) Miao, Z.; Nucci, G.; Amin, N.; Sharma, R.; Mascitti, V.; Tugnait, M.; Vaz, A. D.; Callegari, E.; Kalgutkar, A. S. Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab. Dispos. 2013, 41, 445456,  DOI: 10.1124/dmd.112.049551 .
      (b) Raje, S.; Callegari, E.; Sahasrabudhe, V.; Vaz, A.; Shi, H.; Fluhler, E.; Woolf, E. J.; Schildknegt, K.; Matschke, K.; Alvey, C.; Zhou, S.; Papadopoulos, D.; Fountaine, R.; Saur, D.; Terra, S. G.; Stevens, L.; Gaunt, D.; Cutler, D. L. Novel application of the two-period microtracer approach to determine absolute oral bioavailability and fraction absorbed of ertugliflozin. Clin. Transl. Sci. 2018, 11, 405411,  DOI: 10.1111/cts.12549 .
      (c) Fediuk, D. J.; Nucci, G.; Dawra, V. K.; Cutler, D. L.; Amin, N. B.; Terra, S. G.; Boyd, R. A.; Krishna, R.; Sahasrabudhe, V. Overview of the clinical pharmacology of ertugliflozin, a novel sodium-glucose cotransporter 2 (SGLT2) inhibitor. Clin. Pharmacokinet. 2020, 59, 949965,  DOI: 10.1007/s40262-020-00875-1
    151. 151
      Yan, Q.; Ding, N.; Li, Y. Synthesis and biological evaluation of novel dioxa-bicycle C-arylglucosides as SGLT2 inhibitors. Carbohydr. Res. 2016, 421, 18,  DOI: 10.1016/j.carres.2015.10.011
    152. 152
      Rendell, M. S. Sotagliflozin: a combined SGLT1/SGLT2 inhibitor to treat diabetes. Expert Rev. Endocrinol. Metab. 2018, 13, 333339,  DOI: 10.1080/17446651.2018.1537779
    153. 153
      Li, Y.; Shi, Z.; Chen, L.; Zheng, S.; Li, S.; Xu, B.; Liu, Z.; Liu, J.; Deng, C.; Ye, F. Discovery of a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (HSK0935) for the treatment of type 2 diabetes. J. Med. Chem. 2017, 60, 41734184,  DOI: 10.1021/acs.jmedchem.6b01818
    154. 154
      Wenzel, S. E.; Kamada, A. K. Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma. Ann. Pharmacother. 1996, 30, 858864,  DOI: 10.1177/106002809603000725
    155. 155
      (a) Delorme, D.; Ducharme, Y.; Brideau, C.; Chan, C. C.; Chauret, N.; Desmarais, S.; Dubé, D.; Falgueyret, J. P.; Fortin, R.; Guay, J.; Hamel, P.; Jones, T. R.; Lépine, C.; Li, C.; McAuliffe, M.; McFarlane, C. S.; Nicoll-Griffith, D. A.; Riendeau, D.; Yergey, J. A.; Girard, Y. Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: structure-activity relationship study directed toward the improvement of metabolic stability. J. Med. Chem. 1996, 39, 39513970,  DOI: 10.1021/jm960301c .
      (b) Hamel, P.; Riendeau, D.; Brideau, C.; Chan, C.-C.; Desmarais, S.; Delorme, D.; Dube, D.; Ducharme, Y.; Ethier, D.; Grimm, E.; Falgueyret, J.-P.; Guay, J.; Jones, T. R.; Kwong, E.; McFarlane, C. S.; Piechuta, H.; Roumi, M.; Tagari, P.; Young, R. N.; Girard, Y. Substituted (pyridylmethoxy)naphthalenes as potent and orally active 5-lipoxygenase inhibitor. synthesis, biological profile, and pharmacokinetics of L-739,010. J. Med. Chem. 1997, 40, 28662875,  DOI: 10.1021/jm970046b
    156. 156
      (a) Chauret, N.; Nicoll-Griffith, D.; Friesen, R.; Li, C.; Trimble, L.; Dubé, D.; Fortin, R.; Girard, Y.; Yergey, J. Microsomal metabolism of the 5-lipoxygenase inhibitors L-746,530 and L-739,010 to reactive intermediates that covalently bind to protein: the role of the 6,8-dioxabicyclo[3.2.1]octanyl moiety. Drug Metab. Dispos. 1995, 23, 13251334.
      (b) Zhang, K. E.; Naue, J. A.; Arison, B.; Vyas, K. P. Microsomal metabolism of the 5-lipoxygenase inhibitor L-739,010: evidence for furan bioactivation. Chem. Res. Toxicol. 1996, 9, 547554,  DOI: 10.1021/tx950183g
    157. 157
      Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.; Ahn, K.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. Discovery of tofogliflozin, a novel C-arylglucoside with an O-spiroketal ring system, as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2012, 55, 78287840,  DOI: 10.1021/jm300884k
    158. 158
      (a) Lv, B.; Xu, B.; Feng, Y.; Peng, K.; Xu, G.; Du, J.; Zhang, L.; Zhang, W.; Zhang, T.; Zhu, L.; Ding, H.; Sheng, Z.; Welihinda, A.; Seed, B.; Chen, Y. Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 68776881,  DOI: 10.1016/j.bmcl.2009.10.088 .
      (b) Kasahara-Ito, N.; Fukase, H.; Ogama, Y.; Saito, T.; Ohba, Y.; Shimada, S.; Takano, Y.; Ichihara, T.; Terao, K.; Nakamichi, N.; Kumagai, Y.; Ikeda, S. Pharmacokinetics and pharmacodynamics of tofogliflozin (a selective SGLT2 inhibitor) in healthy male subjects. Drug Res. 2017, 67, 349357,  DOI: 10.1055/s-0043-104779
    159. 159
      (a) Seward, E. M.; Carlson, E.; Harrison, T.; Haworth, K. E.; Herbert, R.; Kelleher, F. J.; Kurtz, M. M.; Moseley, J.; Owen, S. N.; Owens, A. P.; Sadowski, S. J.; Swain, C. J.; Williams, B. J. Spirocyclic NK1 antagonists I: [4.5] and [5.5]-spiroketals. Bioorg. Med. Chem. Lett. 2002, 12, 25152518,  DOI: 10.1016/S0960-894X(02)00506-1 .
      (b) Quach, R.; Furkert, D. P.; Brimble, M. A. Gold Catalysis: Synthesis of Spiro, Bridged, and Fused Ketal Natural Products. Org. Biomol. Chem. 2017, 15, 30983104,  DOI: 10.1039/C7OB00496F .
      (c) Choi, K. W.; Brimble, M. A. Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffolds. Org. Biomol. Chem. 2009, 7, 142436,  DOI: 10.1039/b818314g .
      (d) Zhang, F. M.; Zhang, S. Y.; Tu, Y. Q. Recent progress in the isolation, bioactivity, biosynthesis, and total synthesis of natural spiroketals. Nat. Prod. Rep. 2018, 35, 75104,  DOI: 10.1039/C7NP00043J .
      (e) Lenci, E. Synthesis and biological properties of spiroacetal-containing small molecules. Small Molecule Drug Discovery 2020, 225245,  DOI: 10.1016/B978-0-12-818349-6.00008-X
    160. 160
      (a) Ghosh, A. K.; Dawson, Z. L.; Mitsuya, H. Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV. Bioorg. Med. Chem. 2007, 15, 75767580,  DOI: 10.1016/j.bmc.2007.09.010 .
      (b) Ghosh, A. K.; Sridhar, P. R.; Kumaragurubaran, N.; Koh, Y.; Weber, I. T.; Mitsuya, H. Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of HIV protease inhibitors that combat drug resistance. ChemMedChem 2006, 1, 939950,  DOI: 10.1002/cmdc.200600103 .
      (c) Ghosh, A. K. Harnessing nature’s Insight: design of aspartyl protease inhibitors from treatment of drug-resistant HIV to Alzheimer’s disease. J. Med. Chem. 2009, 52, 21632176,  DOI: 10.1021/jm900064c
    161. 161
      Vermeir, M.; Lachau-Durand, S.; Mannens, G.; Cuyckens, F.; van Hoof, B.; Raoof, A. Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjects. Drug Metab. Dispos. 2009, 37, 809820,  DOI: 10.1124/dmd.108.024109
    162. 162
      Sadler, B. M.; Chittick, G. E.; Polk, R. E.; Slain, D.; Kerkering, T. M.; Studenberg, S. D.; Lou, Y.; Moore, K. H.; Woolley, J.; Stein, D. S. Metabolic disposition and pharmacokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjects. J. Clin. Pharmacol. 2001, 41, 386396,  DOI: 10.1177/00912700122010249
    163. 163
      (a) Ghosh, A. K.; Xu, C.; Rao, K. V.; Baldridge, A.; Agniswamy, J.; Wang, Y.; Weber, I. T.; Aoki, M.; Miguel, S.; Amano, M.; Mitsuya, H. Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors. ChemMedChem 2010, 5, 18501854,  DOI: 10.1002/cmdc.201000318 .
      (b) Zhang, H.; Wang, Y.; Shen, C.; Agniswamy, J.; Rao, K. V.; Xu, C.; Ghosh, A. K.; Harrison, R. W.; Weber, I. T. Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL0519) fills the S2 binding pocket of selected mutants of HIV-1 protease. J. Med. Chem. 2013, 56, 10741083,  DOI: 10.1021/jm301519z .
      (c) Ghosh, A. K.; Rao, K. V.; Nyalapatla, P. R.; Osswald, H. L.; Martyr, C. D.; Aoki, M.; Hayashi, H.; Agniswamy, J.; Wang, Y.; Bulut, H.; Das, D.; Weber, I. T.; Mitsuya, H. Design and development of highly potent HIV-1 protease inhibitors with a crown-like oxotricyclic core as the P2-ligand to combat multidrug-resistant HIV variants. J. Med. Chem. 2017, 60, 42674278,  DOI: 10.1021/acs.jmedchem.7b00172
    164. 164
      (a) Chang, Z. The discovery of Qinghaosu (artemisinin) as an effective anti-malaria drug: A unique China story. Sci. China: Life Sci. 2016, 59, 8188,  DOI: 10.1007/s11427-015-4988-z .
      (b) Cui, L.; Su, X. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev. Anti-Infect. Ther. 2009, 7, 9991013,  DOI: 10.1586/eri.09.68 .
      (c) Fernández-Álvaro, E.; Hong, W. D.; Nixon, G. L.; O’Neill, P. M.; Calderón, F. Antimalarial chemotherapy: natural product inspired development of preclinical and clinical candidates with diverse mechanisms of action. J. Med. Chem. 2016, 59, 55875603,  DOI: 10.1021/acs.jmedchem.5b01485 .
      (d) Wells, T. N.; Huijsduijnen, R. H.; Voorhis, W. C. Malaria medicines: a glass half full?. Nat. Rev. Drug Discovery 2015, 14, 424442,  DOI: 10.1038/nrd4573 .
      (e) Sharma, B.; Singh, P.; Singh, A. K.; Awasthi, S. K. Advancement of chimeric hybrid drugs to cure malaria infection: an overview with special emphasis on endoperoxide pharmacophores. Eur. J. Med. Chem. 2021, 219, 113408,  DOI: 10.1016/j.ejmech.2021.113408
    165. 165
      (a) Zeng, M.; Li, L.; Chen, S.; Li, C.; Liang, X.; Chen, M.; Clardy, J. Chemical transformations of qinghaosu, a peroxidic antimalarial. Tetrahedron 1983, 39, 29412946,  DOI: 10.1016/S0040-4020(01)92155-6 .
      (b) Lin, A. J.; Klayman, D. L.; Hoch, J. M.; Silverton, J. M.; George, C. F. Thermal rearrangement and decomposition products of artemisinin (qinghaosu). J. Org. Chem. 1985, 50, 45044508,  DOI: 10.1021/jo00223a017
    166. 166
      (a) Gomes, G.; Vil, V.; Terent’ev, A.; Alabugin, I. V. Stereoelectronic source of the anomalous stability of bis-peroxides. Chem. Sci. 2015, 6, 67836791,  DOI: 10.1039/C5SC02402A .
      (b) Edwards, J. O.; Pearson, R. G. The factors determining nucleophilic reactivities. J. Am. Chem. Soc. 1962, 84, 1624,  DOI: 10.1021/ja00860a005 .
      (c) Hoz, S.; Buncel, E. The α-effect: a critical examination of the phenomenon and its origin. Isr. J. Chem. 1985, 26, 313319,  DOI: 10.1002/ijch.198500113 .
      (d) Buncel, E.; Um, I. The α-effect and its modulation by solvent. Tetrahedron 2004, 60, 78017825,  DOI: 10.1016/j.tet.2004.05.006
    167. 167
      Haynes, R. K.; Krishna, S. Artemisinins: activities and actions. Microbes Infect. 2004, 6, 13391346,  DOI: 10.1016/j.micinf.2004.09.002
    168. 168
      (a) O’Neill, P. M.; Barton, V. E.; Ward, S. A. The molecular mechanism of action of artemisinin - the debate continues. Molecules 2010, 15, 17051721,  DOI: 10.3390/molecules15031705 .
      (b) Li, Z.; Li, Q.; Wu, J.; Wang, M.; Yu, J. Artemisinin and its derivatives as a repurposing anticancer agent: what else do we need to do?. Molecules 2016, 21, 1331,  DOI: 10.3390/molecules21101331 .
      (c) Cui, L.; Su, X. Z. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev. Anti-Infect. Ther. 2009, 7, 9991013,  DOI: 10.1586/eri.09.68 .
      (d) Wang, J.; Zhang, C. J.; Chia, W.; Loh, C.; Li, Z.; Lee, Y. M.; He, Y.; Yuan, L. X.; Lim, T. K.; Liu, M.; Liew, C. X.; Lee, Y. Q.; Zhang, J.; Lu, N.; Lim, C. T.; Hua, Z. C.; Liu, B.; Shen, H. M.; Tan, K. S.; Lin, Q. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat. Commun. 2015, 6, 10111,  DOI: 10.1038/ncomms10111
    169. 169
      (a) Lin, A. J.; Klayman, D. L.; Milhous, W. K. Antimalarial activity of new water-soluble dihydroartemisinin derivatives. J. Med. Chem. 1987, 30, 21472150,  DOI: 10.1021/jm00394a037 .
      (b) Lin, A. J.; Zikry, A. B.; Kyle, D. E. Antimalarial activity of new dihydroartemisinin derivatives. 7. 4-(p-Substituted phenyl)-4(R or S)-[10(δ. or β)-dihydroartemisininoxy]butyric acids. J. Med. Chem. 1997, 40, 13961400,  DOI: 10.1021/jm9607919
    170. 170
      Jung, M.; Lee, S. Stability of acetal and non acetal-type analogues of artemisinin in simulated stomach acid. Bioorg. Med. Chem. Lett. 1998, 8, 10031006,  DOI: 10.1016/S0960-894X(98)00160-7
    171. 171
      Jung, M.; Lee, K.; Kendrick, H.; Robinson, B. L.; Croft, S. L. Synthesis, stability, and antimalarial activity of new hydrolytically stable and water-soluble (+)-deoxoartelinic acid. J. Med. Chem. 2002, 45, 49404944,  DOI: 10.1021/jm020244p
    172. 172
      Singh, C.; Verma, V. P.; Hassam, M.; Singh, A. S.; Naikade, N. K.; Puri, S. K. New orally active amino- and hydroxy-functionalized 11-azaartemisinins and their derivatives with high order of antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice. J. Med. Chem. 2014, 57, 24892497,  DOI: 10.1021/jm401774f
    173. 173
      Haynes, R. K.; Fugmann, B.; Stetter, J.; Rieckmann, K.; Heilmann, H.; Chan, H.; Cheung, M.; Lam, W.; Wong, H.; Croft, S. L.; Vivas, L.; Rattray, L.; Stewart, L.; Peters, W.; Robinson, B. L.; Edstein, M. D.; Kotecka, B.; Kyle, D. E.; Beckermann, B.; Gerisch, M.; Radtke, M.; Schmuck, G.; Steinke, W.; Wollborn, U.; Schmeer, K.; Romer, A. Artemisone - a highly active antimalarial drug of the artemisinin class. Angew. Chem., Int. Ed. 2006, 45, 20822088,  DOI: 10.1002/anie.200503071
    174. 174
      Wang, X.; Dong, Y.; Wittlin, S.; Charman, S. A.; Chiu, F. C.; Chollet, J.; Katneni, K.; Mannila, J.; Morizzi, J.; Ryan, E.; Scheurer, C.; Steuten, J.; Tomas, J. S.; Snyder, C.; Vennerstrom, J. L. Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. J. Med. Chem. 2013, 56, 25472555,  DOI: 10.1021/jm400004u
    175. 175
      (a) Benoit-Vical, F.; Lelievre, J.; Berry, A.; Deymier, C.; Dechy-Cabaret, O.; Cazelles, J.; Loup, C.; Robert, A.; Magnaval, J.; Meunier, B. Trioxaquines are new antimalarial agents active on all erythrocytic forms, including gametocytes. Antimicrob. Agents Chemother. 2007, 51, 14631472,  DOI: 10.1128/AAC.00967-06 .
      (b) Cosledan, F.; Fraisse, L.; Pellet, A.; Guillou, F.; Mordmuller, B.; Kremsner, P. G.; Moreno, A.; Mazier, D.; Maffrand, J.-P.; Meunier, B. Selection of a trioxaquine as an antimalarial drug candidate. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 1757917584,  DOI: 10.1073/pnas.0804338105 .
      (c) Waseem, Y.; Hasan, C. A.; Ahmed, F. Artemisinin: A promising adjunct for cancer therapy. Cureus. 2018, 10 (11), e3628  DOI: 10.7759/cureus.3628 .
      (d) Fröhlich, T.; Çapcı, K. A.; Reiter, C.; Tsogoeva, S. B. Artemisinin-derived dimers: potent antimalarial and anticancer agents. J. Med. Chem. 2016, 59 (16), 736088,  DOI: 10.1021/acs.jmedchem.5b01380 .
      (e) Singh, N. P.; Lai, H. C.; Park, J. S.; Gerhardt, T. E.; Kim, B. J.; Wang, S.; Sasaki, T. Effects of artemisinin dimers on rat breast cancer cells in vitro and in vivo. Anticancer Res. 2011, 31 (12), 41114.
      (f) Moses, B. S.; McCullough, S.; Fox, J. M.; Mott, B. T.; Bentzen, S. M.; Kim, M.; Tyner, J. W.; Lapidus, R. G.; Emadi, A.; Rudek, M. A.; Kingsbury, T. J.; Civin, C. Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclax. Blood Adv. 2021, 5 (3), 711724,  DOI: 10.1182/bloodadvances.2020003429 .
      (g) Cheng, C.; Wang, T.; Song, Z.; Peng, L.; Gao, M.; Hermine, O.; Rousseaux, S.; Khochbin, S.; Mi, J. Q.; Wang, J. Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044. Cancer Med. 2018, 7 (2), 380396,  DOI: 10.1002/cam4.1276
    176. 176
      (a) Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.; Chiu, F. C.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam, M.; Tomas, J. S.; Scheurer, C.; Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N. Identification of an antimalarial synthetic trioxolane drugdevelopment candidate. Nature 2004, 430, 900904,  DOI: 10.1038/nature02779 .
      (b) Dong, Y.; Tang, Y.; Chollet, J.; Matile, H.; Wittlin, S.; Charman, S. A.; Charman, W. N.; Tomas, J. S.; Scheurer, C.; Snyder, C. Effect of functional group polarity on the antimalarial activity of spiro and dispiro-1,2,4-trioxolanes. Bioorg. Med. Chem. 2006, 14, 63686382,  DOI: 10.1016/j.bmc.2006.05.041 .
      (c) Kim, H. S.; Hammill, J. T.; Guy, R. K. Seeking the elusive long-acting ozonide: discovery of artefenomel (OZ439). J. Med. Chem. 2017, 60, 26512653,  DOI: 10.1021/acs.jmedchem.7b00299 .
      (d) Dong, Y.; Wang, X.; Kamaraj, S.; Bulbule, V. J.; Chiu, F. C.; Chollet, J.; Dhanasekaran, M.; Hein, C. D.; Papastogiannidis, P.; Morizzi, J.; Shackleford, D. M.; Barker, H.; Ryan, E.; Scheurer, C.; Tang, Y.; Zhao, Q.; Zhou, L.; White, K. L.; Urwyler, H.; Charman, W. N.; Matile, H.; Wittlin, S.; Charman, S. A.; Vennerstrom, J. L. Structure-activity relationship of the antimalarial ozonide artefenomel (OZ439). J. Med. Chem. 2017, 60, 26542668,  DOI: 10.1021/acs.jmedchem.6b01586 .
      (e) Phyo, A. P.; Jittamala, P.; Nosten, F. N.; Pukrittayakamee, S.; Imwong, M.; White, N. J.; Duparc, S.; Macintyre, F.; Baker, M.; Möhrle, J. J. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect. Dis. 2016, 16, 6169,  DOI: 10.1016/S1473-3099(15)00320-5
    177. 177
      Opsenica, I.; Opsenica, D.; Smith, K. S.; Milhous, W. K.; Solaja, B. A. Chemical stability of the peroxide bond enables diversified synthesis of potent tetraoxane antimalarials. J. Med. Chem. 2008, 51, 22612266,  DOI: 10.1021/jm701417a
    178. 178
      (a) Ellis, G. L.; Amewu, R.; Sabbani, S.; Stocks, P. A.; Shone, A.; Stanford, D.; Gibbons, P.; Davies, J.; Vivas, L.; Charnaud, S.; Bongard, E.; Hall, C.; Rimmer, K.; Lozanom, S.; Jesús, M.; Gargallo, D.; Ward, S. A.; O’Neill, P. M. Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles. J. Med. Chem. 2008, 51, 21702177,  DOI: 10.1021/jm701435h .
      (b) O’Neill, P. M.; Amewu, R. K.; Nixon, G. L.; El Garah, F. B.; Mungthin, M.; Chadwick, J.; Shone, A. E.; Vivas, L.; Lander, H.; Barton, V.; Muangnoicharoen, S.; Bray, P. G.; Davies, J.; Park, B. K.; Wittlin, S.; Brun, R.; Preschel, M.; Zhang, K.; Ward, S. A. Identification of a 1,2,4,5-tetraoxane antimalarial drug-development candidate (RKA182) with superior properties to the semisynthetic artemisinins. Angew. Chem., Int. Ed. 2010, 49, 56935697,  DOI: 10.1002/anie.201001026 .
      (c) Marti, F.; Chadwick, J.; Amewu, R. K.; Burrell-Saward, H.; Srivastava, A.; Ward, S. A.; Sharma, R.; Berry, N.; O’Neill, P. M. Second generation analogues of RKA182: synthetic tetraoxanes with outstanding in vitro and in vivo antimalarial activities. MedChemComm 2011, 2, 661665,  DOI: 10.1039/c1md00102g .
      (d) O’Neill, P. M.; Amewu, R. K.; Charman, S. A.; Sabbani, S.; Gnadig, N. F.; Straimer, J.; Fidock, D. A.; Shore, E. R.; Roberts, N. L.; Wong, M. H.; Hong, W. D.; Pidathala, C.; Riley, C.; Murphy, B.; Aljayyoussi, G.; Gamo, F. J.; Sanz, L.; Rodrigues, J.; Cortes, C. C.; Herreros, E.; Angulo-Barturen, I.; Jimenez-Dıaz, M. B.; Bazaga, S. F.; Martınez-Martınez, M. S.; Campo, B.; Sharma, R.; Ryan, E.; Shackleford, D. M.; Campbell, S.; Smith, D. A.; Wirjanata, G.; Noviyanti, R.; Price, R. N.; Marfurt, J.; Palmer, M. J.; Copple, I. M.; Mercer, A. E.; Ruecker, A.; Delves, M. J.; Sinden, R. E.; Sieg, P.; Davies, J.; Rochford, R.; Kocken, C. H.; Zeeman, A.; Nixon, G. L.; Biagini, G. A.; Ward, S. A. A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance. Nat. Commun. 2017, 8, 15159,  DOI: 10.1038/ncomms15159
    179. 179
      (a) Counter, F. T.; Ensminger, P. W.; Preston, D. A.; Wu, C. Y.; Greene, J. M.; Felty-Duckworth, A. M.; Paschal, J. W.; Kirst, H. A. Synthesis and antimicrobial evaluation of dirithromycin (AS-E 13. LY237216), a new macrolide antibiotic derived from erythromycin. Antimicrob. Agents Chemother. 1991, 35, 11161126,  DOI: 10.1128/AAC.35.6.1116 .
      (b) Mazzei, T.; Surrenti, C.; Novelli, A.; Biagini, M. R.; Fallani, S.; Cassetta, M. I.; Conti, S.; Surrenti, E. Pharmacokinetics of dirithromycin in patients with mild or moderate cirrhosis. Antimicrob. Agents Chemother. 1999, 43, 15561559,  DOI: 10.1128/AAC.43.7.1556 .
      (c) Sides, G. D.; Cerimele, B. J.; Black, H. R.; Bosch, U.; DeSante, K. A. Pharmacokinetics of dirithromycin. J. Antimicrob. Chemother. 1993, 31, 6575,  DOI: 10.1093/jac/31.suppl_C.65 .
      (d) Shinkai, I.; Ohta, Y. Dirithromycin. Bioorg. Med. Chem. 1996, 4, 521522,  DOI: 10.1016/0968-0896(96)00052-1
    180. 180
      (a) Khabibullina, N. F.; Tereshchenkov, A. G.; Komarova, E. S.; Syroegin, E. A.; Shiriaev, D. I.; Paleskava, A.; Kartsev, V. G.; Bogdanov, A. A.; Konevega, A. L.; Dontsova, O. A.; Sergiev, P. V.; Osterman, I. A.; Polikanov, Y. S. Structure of dirithromycin bound to the bacterial ribosome suggests new ways for rational improvement of macrolides. Antimicrob. Agents Chemother. 2019, 63, e02266  DOI: 10.1128/AAC.02266-18 .
      (b) Pichkur, E. B.; Paleskava, A.; Tereshchenkov, A. G.; Kasatsky, P.; Komarova, E. S.; Shiriaev, D. I.; Bogdanov, A. A.; Dontsova, O. A.; Osterman, I. A.; Sergiev, P. V.; Polikanov, Y. S.; Myasnikov, A. G.; Konevega, A. L. Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the E. coli 70S ribosome. RNA 2020, 26, 715723,  DOI: 10.1261/rna.073817.119
    181. 181
      (a) Wöhr, T.; Wahl, F.; Nefzi, A.; Rohwedder, B.; Sato, T.; Sun, X.; Mutter, M. Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesis. J. Am. Chem. Soc. 1996, 118, 92189227,  DOI: 10.1021/ja961509q .
      (b) Chaume, G.; Barbeau, O.; Lesot, P.; Brigaud, T. Synthesis of 2-trifluoromethyl-1,3-oxazolidines as hydrolytically stable pseudoprolines. J. Org. Chem. 2010, 75, 41354145,  DOI: 10.1021/jo100518t .
      (c) Malquin, N.; Rahgoshay, K.; Lensen, N.; Chaume, G.; Miclet, E.; Brigaud, T. CF2H as a hydrogen bond donor group for the fine tuning of peptide bond geometry with difluoromethylated pseudoprolines. Chem. Commun. 2019, 55, 1248712490,  DOI: 10.1039/C9CC05771D .
      (d) Chaume, G.; Simon, J.; Caupéne, C.; Lensen, N.; Miclet, E.; Brigaud, T. Incorporation of CF3-pseudoprolines into peptides: a methodological study. J. Org. Chem. 2013, 78, 1014410153,  DOI: 10.1021/jo401494q
    182. 182
      (a) Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. M.; Graham, D. J.; Hu, B.; Huang, Q.; Kargman, S.; Kozlowski, J.; Liu, R.; McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.; Wang, D.; Wu, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W. Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem 2013, 8, 19301940,  DOI: 10.1002/cmdc.201300343 .
      (b) Yu, W.; Tong, L.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Coburn, C. A.; Selyutin, O.; Chen, L.; Rokosz, L.; Agrawal, S.; Liu, R.; Curry, S.; McMonagle, P.; Ingravallo, P.; Asante-Appiah, E.; Chen, S.; Kozlowski, J. A. Discovery of chromane containing hepatitis C virus (HCV) NS5A inhibitors with improved potency against resistance-associated variants. J. Med. Chem. 2016, 59, 1022810243,  DOI: 10.1021/acs.jmedchem.6b01234 .
      (c) Tong, L.; Yu, W.; Chen, L.; Selyutin, O.; Dwyer, M. P.; Nair, A. G.; Mazzola, R.; Kim, J.; Sha, D.; Yin, J.; Ruck, R. T.; Davies, R. W.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Liu, R.; Agrawal, S.; Xia, E.; Curry, S.; McMonagle, P.; Bystol, K.; Lahser, F.; Carr, D.; Rokosz, L.; Ingravallo, P.; Chen, S.; Feng, K.; Cartwright, M.; Asante-Appiah, E.; Kozlowski, J. A. Discovery of ruzasvir (MK-8408): a potent, pan-genotype HCV NS5A inhibitor with optimized activity against common resistance-associated polymorphisms. J. Med. Chem. 2017, 60, 290306,  DOI: 10.1021/acs.jmedchem.6b01310 .
      (d) Yu, W.; Tong, L.; Selyutin, O.; Chen, L.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Yin, J.; Ruck, R. T.; Curry, S.; McMonagle, P.; Agrawal, S.; Rokosz, L.; Carr, D.; Ingravallo, P.; Bystol, K.; Lahser, F.; Liu, R.; Chen, S.; Feng, K.; Cartwright, M.; Asante-Appiah, E.; Kozlowski, J. A. Discovery of MK-6169, a potent pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. J. Med. Chem. 2018, 61, 39844003,  DOI: 10.1021/acs.jmedchem.7b01927 .
      (e) https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208261Orig1s000PharmR.pdf (accessed April 2, 2021.)
    183. 183
      (a) Reading, C.; Cole, M. Clavulanic acid: a β-lactamase-inhibiting β-lactam from Streptomyces clavuligerus. Antimicrob. Agents Chemother. 1977, 11, 852857,  DOI: 10.1128/AAC.11.5.852 .
      (b) Buynak, J. D. Understanding the longevity of the β-lactam antibiotics and of antibiotic/β-lactamase inhibitor combinations. Biochem. Pharmacol. 2006, 71, 930940,  DOI: 10.1016/j.bcp.2005.11.012
    184. 184
      (a) Brown, R. P.; Aplin, R. T.; Schofield, C. J. Inhibition of TEM-2 β-lactamase from Escherichia coli by clavulanic acid: observation of intermediates by electrospray ionization mass spectrometry. Biochemistry 1996, 35, 1242112432,  DOI: 10.1021/bi961044g .
      (b) Imtiaz, U.; Billings, E.; Knox, J. R.; Manavathu, E. K.; Lerner, S. A.; Mobashery, S. Inactivation of class A β-lactamases by clavulanic acid: the role of arginine-244 in a proposed nonconcerted sequence of events. J. Am. Chem. Soc. 1993, 115, 44354442,  DOI: 10.1021/ja00064a003
    185. 185
      Haginaka, J.; Nakagawa, T.; Uno, T. Stability of clavulanic acid in aqueous solutions. Chem. Pharm. Bull. 1981, 29, 33343341,  DOI: 10.1248/cpb.29.3334
    186. 186
      (a) Adam, D.; de Visser, I.; Koeppe, P. Pharmacokinetics of amoxicillin and clavulanic acid administered alone and in combination. Antimicrob. Agents Chemother. 1982, 22, 353357,  DOI: 10.1128/AAC.22.3.353 .
      (b) Navarro, A. S. New formulations of amoxicillin/clavulanic acid. Clin. Pharmacokinet. 2005, 44, 10971115,  DOI: 10.2165/00003088-200544110-00001 .
      (c) De Velde, F.; De Winter, B. C. M.; Koch, B. C. P.; Van Gelder, T.; Mouton, J. W. and the COMBACTE-NET consortium. Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis. J. Antimicrob. Chemother. 2018, 73, 469476,  DOI: 10.1093/jac/dkx376
    187. 187
      (a) Krishnan, B. R.; James, K. D.; Polowy, K.; Bryant, B.; Vaidya, A.; Smith, S.; Laudeman, C. P. CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. J. Antibiot. 2017, 70, 130135,  DOI: 10.1038/ja.2016.89 .
      (b) Sofjan, A. K.; Mitchell, A.; Shah, D. N.; Nguyen, T.; Sim, M.; Trojcak, A.; Beyda, N. D.; Garey, K. W. Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy. J. Global Antimicrob. Resist. 2018, 14, 5864,  DOI: 10.1016/j.jgar.2018.02.013
    188. 188
      Kofla, G.; Ruhnke, M. Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis: review of the literature. Eur. J. Med.Res. 2011, 16, 159166,  DOI: 10.1186/2047-783X-16-4-159
    189. 189
      (a) Johns, B. A.; Kawasuji, T.; Weatherhead, J. G.; Taishi, T.; Temelkoff, D. P.; Yoshida, H.; Akiyama, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Jeffrey, J.; Foster, S. A.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Johnson, M. N.; Garvey, E. P.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744). J. Med. Chem. 2013, 56, 59015916,  DOI: 10.1021/jm400645w .
      (b) Kawasuji, T.; Johns, B. A.; Yoshida, H.; Weatherhead, J. G.; Akiyama, T.; Taishi, T.; Taoda, Y.; Mikamiyama-Iwata, M.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Garvey, E. P.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles. J. Med. Chem. 2013, 56, 11241135,  DOI: 10.1021/jm301550c .
      (c) Kawasuji, T.; Johns, B. A.; Yoshida, H.; Taishi, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors. 1. Molecular design and establishment of an advanced two-metal binding pharmacophore. J. Med. Chem. 2012, 55, 87358744,  DOI: 10.1021/jm3010459
    190. 190
      (a) Tsiang, M.; Jones, G. S.; Goldsmith, J.; Mulato, A.; Hansen, D.; Kan, E.; Tsai, L.; Bam, R. A.; Stepan, G.; Stray, K. M.; Niedziela-Majka, A.; Yant, S. R.; Yu, H.; Kukolj, G.; Cihlar, T.; Lazerwith, S. E.; White, K. L.; Jin, H. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob. Agents Chemother. 2016, 60, 70867097,  DOI: 10.1128/AAC.01474-16 .
      (b) Lazerwith, S. E.; Cai, R.; Chen, X.; Chin, G.; Desai, M. C.; Eng, S.; Jacques, R.; Ji, M.; Jones, G.; Martin, H.; McMahon, C.; Mish, M.; Morganelli, P.; Mwangi, J.; Pyun, H.; Schmitz, U.; Stepan, G.; Szwarcberg, J.; Tang, J.; Tsiang, M.; Wang, J.; Wang, K.; White, K.; Wiser, L.; Zack, J.; Jin, H. Discovery of bictegravir (GS-9883), a novel, unboosted, once-daily HIV-1 integrase strand transfer inhibitor (INSTI) with improved pharmacokinetics and in vitro resistance profile. ASM Microbe: Boston, MA, 2016.
    191. 191
      Deeks, E. D. Bictegravir/emtricitabine/tenofovir alafenamide: a review in HIV-1 infection. Drugs 2018, 78, 18171828,  DOI: 10.1007/s40265-018-1010-7
    192. 192
      (a) Wu, Y.-J.; Guernon, J.; Rajamani, R.; Toyn, J. H.; Ahlijanian, M. K.; Albright, C. F.; Muckelbauer, J.; Chang, C.; Camac, D.; Macor, J. E.; Thompson, L. A. Discovery of furo[2,3-d][1,3]thiazinamines as β-amyloid cleaving enzyme-1 (BACE1) inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 57295731,  DOI: 10.1016/j.bmcl.2016.10.055 .
      (b) Wu, Y.-J.; Guernon, J.; Park, H.; Thompson, L. A. Expedient synthesis of fluoro[2,3-d[1,3]thiazinamines and pyrano-[2,3-d][1,3]thiazinamines from enones and thiourea. J. Org. Chem. 2016, 81, 33863390,  DOI: 10.1021/acs.joc.5b02705
    193. 193
      Futamura, A.; Suzuki, R.; Tamura, Y.; Kawamoto, H.; Ohmichi, M.; Hino, N.; Tokumaru, Y.; Kirinuki, S.; Hiyoshi, T.; Aoki, T.; Kambe, D.; Nozawa, D. Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia. Bioorg. Med. Chem. 2020, 28, 115489,  DOI: 10.1016/j.bmc.2020.115489
    194. 194
      (a) Miller, T. W.; Goegelman, R. T.; Weston, R. G.; Putter, I.; Wolf, F. J. Cephamycins, a new family of β-lactam antibiotics. II. Isolation and chemical characterization. Antimicrob. Agents Chemother. 1972, 2, 132135,  DOI: 10.1128/AAC.2.3.132 .
      (b) Stapley, E. O.; Birnbaum, J.; Miller, A. K.; Wallick, H.; Hendlin, D.; Woodruff, H. B. Cefoxitin and cephamycins: microbiological studies. Clin. Infect. Dis. 1979, 1, 7387,  DOI: 10.1093/clinids/1.1.73
    195. 195
      Brites, L. M.; Oliveira, L. M.; Barboza, M. Kinetic study on cephamycin C degradation. Appl. Biochem. Appl. Biochem. Biotechnol. 2013, 171, 21212128,  DOI: 10.1007/s12010-013-0502-x
    196. 196
      (a) Hagmann, W. K.; Thompson, K. R.; Shah, S. K.; Finke, P. E.; Ashe, B. M.; Weston, H.; Maycock, A. L.; Doherty, J. B. The effect of N-acyl substituents on the stability of monocyclic β-lactam inhibitors of human leukocyte elastase. Bioorg. Med. Chem. Lett. 1992, 2, 681684,  DOI: 10.1016/S0960-894X(00)80390-X .
      (b) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L. Orally active β-lactam inhibitors of human leukocyte elastase. 3. Stereospecific synthesis and structure-activity relationships for 3,3-dialkylazetidin-2-ones. J. Med. Chem. 1995, 38, 24492462,  DOI: 10.1021/jm00013a021 .
      (c) Doherty, J. B.; Shah, S. K.; Finke, P. E.; Dorn, C. P.; Hagmann, W. K.; Hale, J. J.; Kissinger, A. L.; Thompson, K. R.; Brause, K.; Chandler, G. O. Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: a potent, orally active monocyclic β-lactam inhibitor of human polymorphonuclear leukocyte elastase. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 87278731,  DOI: 10.1073/pnas.90.18.8727 .
      (d) Vincent, S. H.; Painter, S. K.; Luffer-Atlas, D.; Karanam, B. V.; McGowan, E.; Cioffe, C.; Doss, G.; Chiu, S. Orally active inhibitors of human leukocyte elastase. II. Disposition of L-694,458 in rats and rhesus monkeys. Drug Metab. Dispos. 1997, 25, 932939
    197. 197
      Halas, C. J. Eszopiclone. Am. J. Health-Syst. Pharm. 2006, 63, 4148,  DOI: 10.2146/ajhp050357
    198. 198
      (a) Shelton, J.; Lu, X.; Hollenbaugh, J. A.; Cho, J. H.; Amblard, F.; Schinazi, R. F. Metabolism, biochemical actions, and chemical synthesis of anticancer nucleosides, nucleotides, and base analogues. Chem. Rev. 2016, 116, 1437914455,  DOI: 10.1021/acs.chemrev.6b00209 .
      (b) Seley-Radtke, K.; Yates, M. K. The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part I: Early structural modifications to the nucleoside scaffold. Antiviral Res. 2018, 154, 6686,  DOI: 10.1016/j.antiviral.2018.04.004 .
      (c) Seley-Radtke, K.; Yates, M. K. The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold. Antiviral Res. 2019, 162, 521,  DOI: 10.1016/j.antiviral.2018.11.016 .
      (d) Li, G.; Yue, T.; Zhang, P.; Gu, W.; Gao, L.-J.; Tan, L. Drug discovery of nucleos(t)ide antiviral agents: dedicated to Prof. Dr. Erik De Clercq on occasion of his 80th birthday. Molecules 2021, 26, 923,  DOI: 10.3390/molecules26040923 .
      (e) Guinan, M.; Benckendorff, C.; Smith, M.; Miller, G. J. Recent advances in the chemical synthesis and evaluation of anticancer nucleoside analogues. Molecules 2020, 25, 2050,  DOI: 10.3390/molecules25092050
    199. 199
      (a) Garrett, E. R.; Seydel, J. K.; Sharpen, A. J. The acid-catalyzed solvolysis of pyrimidine nucleosides. J. Org. Chem. 1966, 31, 22192227,  DOI: 10.1021/jo01345a033 .
      (b) Zoltewicz, J. A.; Clark, D. F.; Sharpless, T. W.; Grahe, G. Kinetics and mechanism of the acid-catalyzed hydrolysis of some purine nucleosides. J. Am. Chem. Soc. 1970, 92, 17411750,  DOI: 10.1021/ja00709a055 .
      (c) Garrett, E. R.; Mehta, P. Solvolysis of adenine nucleosides. I. Effects of sugars and adenine substituents on acid solvolyses. J. Am. Chem. Soc. 1972, 94, 85328541,  DOI: 10.1021/ja00779a040 .
      (d) York, J. L. Effect of the structure of the glycon on the acid-catalyzed hydrolysis of adenine nucleosides. J. Org. Chem. 1981, 46, 21712173,  DOI: 10.1021/jo00323a040 .
      (e) Gates, K. S. An overview of chemical processes that damage cellular DNA: spontaneous hydrolysis, alkylation, and reactions with radicals. Chem. Res. Toxicol. 2009, 22, 17471760,  DOI: 10.1021/tx900242k
    200. 200
      Pogocki, D.; Schöneich, C. Chemical stability of nucleic acid-derived drugs. J. Pharm. Sci. 2000, 89, 443456,  DOI: 10.1002/(SICI)1520-6017(200004)89:4<443::AID-JPS2>3.3.CO;2-N
    201. 201
      (a) Minami, T.; Nakagawa, H.; Nabeshima, M.; Kadota, E.; Namikawa, K.; Kawaki, H.; Okazaki, Y. Nephrotoxicity induced by adenine and its analogues: relationship between structure and renal injury. Biol. Pharm. Bull. 1994, 17, 10321037,  DOI: 10.1248/bpb.17.1032 .
      (b) Philips, F. S.; Thiersch, J. B.; Bendich, A.; Borgatta, M. Adenine intoxication in relation to in vivo formation and deposition of 2,8-dioxyadenine in renal tubules. J. Pharmacol. Exp. Ther. 1952, 104, 2030
    202. 202
      (a) Frank, K. B.; Connell, E. V.; Holman, M. J.; Huryn, D. M.; Sluboski, B. C.; Tam, S. Y.; Todaro, L. J.; Weigele, M.; Richman, D. D.; Mitsuya, H.; Broder, S.; Sim, I. S. Anabolism and mechanism of action of Ro24–5098, an isomer of 2′,3′-dideoxyadenosine (ddA) with anti-HIV activity. Ann. N. Y. Acad. Sci. 1990, 616, 408414,  DOI: 10.1111/j.1749-6632.1990.tb17860.x .
      (b) Andrade, C. H.; de Freitas, L. M.; de Oliveira, V. Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism. Braz. J. Pharm. Sci. 2011, 47, 209230,  DOI: 10.1590/S1984-82502011000200003 .
      (c) Martin, J. C.; Hitchcock, M. J. M.; De Clercq, E.; Prusoff, W. H. Early nucleoside reverse transcriptase inhibitors for the treatment of HIV: A brief history of stavudine (D4T) and its comparison with other dideoxynucleosides. Antiviral Res. 2010, 85, 3438,  DOI: 10.1016/j.antiviral.2009.10.006
    203. 203
      Hirt, D.; Bardin, C.; Diagbouga, S.; Nacro, B.; Hien, H.; Zoure, E.; Rouet, F.; Ouiminga, A.; Urien, S.; Foulongne, V.; Van De Perre, P.; Treuyer, J.; Msellati, P. Didanosine population pharmacokinetics in west african human immunodeficiency virus-infected children administered once-daily tablets in relation to efficacy after one year of treatment. Antimicrob. Agents Chemother. 2009, 53, 43994406,  DOI: 10.1128/AAC.01187-08
    204. 204
      (a) Kelley, J. A.; Litterst, C. L.; Roth, J. S.; Vistica, D. T.; Poplack, D. G.; Cooney, D. A.; Nadkarni, M.; Balis, F. M.; Broder, S.; Johns, D. G. The disposition and metabolism of 2′,3′-dideoxycytidine, an in vitro inhibitor of human T-lymphotrophic virus type III infectivity, in mice and monkeys. Drug Metab. Dispos. 1987, 15, 595601.
      (b) Klecker, R. W., Jr.; Collins, J. M.; Yarchoan, R. C.; Thomas, R.; McAtee, N.; Broder, S.; Myers, C. E. Pharmacokinetics of 2′,3′-dideoxycytidine in patients with AIDS and related disorders. J. Clin. Pharmacol. 1988, 28, 837842,  DOI: 10.1002/j.1552-4604.1988.tb03225.x
    205. 205
      (a) Marquez, V. E.; Tseng, C. K.; Mitsuya, H.; Aoki, C.; Kelley, J. A.; Ford, H.; Roth, J. S.; Broder, S.; Johns, D. G.; Driscoll, J. S. Acid-stable 2′-fluoro purine dideoxynucleosides as active agents against HIV. J. Med. Chem. 1990, 33, 978985,  DOI: 10.1021/jm00165a015 .
      (b) Marquez, V. E.; Tseng, C. K.-H.; Kelley, J. A.; Mitsuya, H.; Broder, S.; Roth, J. S.; Driscoll, J. S. 2′,3′-Dideoxy-2′-fluoro-ara-A. An acid-stable purine nucleoside active against human immunodeficiency virus (HIV). Biochem. Pharmacol. 1987, 36, 27192722,  DOI: 10.1016/0006-2952(87)90254-1 .
      (c) Russell, J. W.; Klunk, L. J. Comparative pharmacokinetics of new anti-HIV agents: 2′, 3′-dideoxyadenosine and 2′, 3′-dideoxyinosine. Biochem. Pharmacol. 1989, 38, 13851388,  DOI: 10.1016/0006-2952(89)90176-7
    206. 206
      (a) Liu, P.; Sharon, A.; Chu, C. K. Fluorinated nucleosides: synthesis and biological implication. J. Fluorine Chem. 2008, 129, 743766,  DOI: 10.1016/j.jfluchem.2008.06.007 .
      (b) Wójtowicz-Rajchel, H. Synthesis and applications of fluorinated nucleoside analogues. J. Fluorine Chem. 2012, 143, 1148,  DOI: 10.1016/j.jfluchem.2012.06.026
    207. 207
      Rozen, S.; Vints, I.; Lerner, A.; Hod, O.; Brothers, E. N.; Moncho, S. The chemistry of short-lived α-fluorocarbocations. J. Org. Chem. 2021, 86, 38823889,  DOI: 10.1021/acs.joc.0c02731
    208. 208
      Johnson, S. A. Nucleoside analogues in the treatment of haematological malignancies. Expert Opin. Pharmacother. 2001, 2, 929943,  DOI: 10.1517/14656566.2.6.929
    209. 209
      Avramis, V. I.; Plunkett, W. 2-Fluoro-ATP: a toxic metabolite of 9-β-d-arabinoxyl-2-fluroadenine. Biochem. Biophys. Res. Commun. 1983, 113, 3543,  DOI: 10.1016/0006-291X(83)90428-X
    210. 210
      (a) Carson, D. A.; Wasson, D. B.; Esparza, L. M.; Carrera, C. J.; Kipps, T. J.; Cottam, H. B. Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine. Proc. Natl. Acad. Sci. U. S. A. 1992, 89, 29702974,  DOI: 10.1073/pnas.89.7.2970 .
      (b) Lindemalm, S.; Liliemark, J.; Juliusson, J.; Larsson, R.; Albertioni, F. Cytotoxicity and pharmacokinetics of cladribine metabolite, 2-chloroadenine, in patients with leukemia. Cancer Lett. 2004, 210, 171177,  DOI: 10.1016/j.canlet.2004.03.007
    211. 211
      (a) Chilman-Blair, K.; Mealy, N. E.; Castaner, J. Clofarabine: treatment of acute leukemia. Drugs Future 2004, 29, 112120,  DOI: 10.1358/dof.2004.029.02.776206 .
      (b) Bonate, P.; Arthaud, L.; Cantrell, W.; Stephenson, K.; Secrist, J. A.; Weitman, S. Discovery and development of clofarabine: a nucleoside analogue for treating cancer. Nat. Rev. Drug Discovery 2006, 5, 855863,  DOI: 10.1038/nrd2055 .
      (c) Montgomery, J. A.; Shortnacy-Fowler, A. T.; Clayton, S. D.; Riordan, J. M.; Secrist, J. A. Synthesis and biologic activity of 2′-fluoro-2-halo derivatives of 9-β-d-arabinofuranosyladenine. J. Med. Chem. 1992, 35, 397401,  DOI: 10.1021/jm00080a029 .
      (d) Xie, C.; Plunke, W. Metabolism and actions of 2-chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine in human lymphoblastoid cells. Cancer Res. 1995, 55, 28472852.
      (e) Faderl, S.; Garcia-Manero, G.; Estrov, Z.; Ravandi, F.; Borthakur, G.; Cortes, J. E.; O’Brien, S.; Gandhi, V.; Plunkett, W.; Byrd, A.; Kwari, M.; Kantarjian, H. M. Oral clofarabine in the treatment of patients with higher-risk myelodysplastic syndrome. J. Clin. Oncol. 2010, 28, 27552760,  DOI: 10.1200/JCO.2009.26.3509 .
      (f) Hermann, R.; Karlsson, M. O.; Novakovic, A. M.; Terranova, N.; Fluck, M.; Munafo, A. The clinical pharmacology of cladribine tablets for the treatment of relapsing multiple sclerosis. Clin. Pharmacokinet. 2019, 58, 283297,  DOI: 10.1007/s40262-018-0695-9
    212. 212
      (a) Bolwell, B. J.; Cassileth, P. A.; Gale, R. P. High dose cytarabine: a review. Leukemia 1988, 2, 253260.
      (b) Capizzi, R. L.; White, J. C.; Powell, B. L.; Perrino, F. Effect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabine. Semin. Hematol. 1991, 28, 5469
    213. 213
      (a) Bergmann, W.; Feeney, R. J. Contributions to the study of marine products. The nucleosides of sponges. J. Org. Chem. 1951, 16, 981987,  DOI: 10.1021/jo01146a023 .
      (b) Bergmann, W.; Burke, D. C. Contributions to the study of marine products. The nucleosides of sponges. III. Spongothymidine and spongouridine. J. Org. Chem. 1955, 20, 15011507,  DOI: 10.1021/jo01128a007 .
      (c) Khalifa, S. A. M.; Elias, N.; Farag, M. A.; Chen, L.; Saeed, A.; Hegazy, M.-E. F.; Moustafa, M. S.; Abd El-Wahed, A.; Al-Mousawi, S. M.; Musharraf, S. G.; Chang, F.-R.; Iwasaki, A.; Suenaga, K.; Alajlani, M.; Goransson, U.; El-Seedi, H. R. Marine natural products: a source of novel anticancer drugs. Mar. Drugs 2019, 17, 491,  DOI: 10.3390/md17090491 .
      (d) Dyshlovoy, S. A.; Honecker, F. Marine compounds and cancer: the first two decades of XXI century. Mar. Drugs 2020, 18, 20,  DOI: 10.3390/md18010020
    214. 214
      (a) Sun, Y.; Sun, J.; Shi, S.; Jing, Y.; Yin, S.; Chen, Y.; Li, G.; Xu, Y.; He, Z. Synthesis, transport and pharmacokinetics of 5′-amino acid ester prodrugs of 1-β-d-arabinofuranosylcytosine. Mol. Pharmaceutics 2009, 6, 315325,  DOI: 10.1021/mp800200a .
      (b) Hamada, A.; Kawaguchi, T.; Nakano, M. Clinical pharmacokinetics of cytarabine formulations. Clin. Pharmacokinet. 2002, 41, 705718,  DOI: 10.2165/00003088-200241100-00002
    215. 215
      Zuckerman, T.; Ram, R.; Akria, L.; Koren-Michowitz, M.; Hoffman, R.; Henig, I.; Lavi, N.; Ofran, Y.; Horowitz, N. A.; Nudelman, O.; Tavor, S.; Yeganeh, S.; Gengrinovitch, S.; Flaishon, L.; Tessler, S.; Ben Yakar, R.; Rowe, J. M. BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a study. Blood Adv. 2019, 3, 37403749,  DOI: 10.1182/bloodadvances.2019000468
    216. 216
      Wright, J. A..; Wilson, D. P..; Fox, J. J. Fluoro sugar analogues of arabinosyl- and xylosylcytosines. J. Med. Chem. 1970, 13, 269272,  DOI: 10.1021/jm00296a024
    217. 217
      Pankiewicz, K. W. Fluorinated nucleosides. Carbohydr. Res. 2000, 327, 87105,  DOI: 10.1016/S0008-6215(00)00089-6
    218. 218
      (a) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. Synthesis of 2-deoxy-2,2-difluoro-d-ribose and 2-deoxy-2,2′-difluoro-d-ribofuranosyl nucleosides. J. Org. Chem. 1988, 53, 24062409,  DOI: 10.1021/jo00246a002 .
      (b) Hertel, L. W.; Kroin, J. S.; Grossman, C. S.; Grindey, G. B.; Dorr, A. F.; Storiolo, A. M. V.; Plunkett, W.; Gandhi, V.; Huang, P. Synthesis and biological activity of 2′,2′-difluorodeoxycytidine (gemcitabine). ACS Symp. Ser. 1996, 639 (Biomedical Frontiers of Fluorine Chemistry), 265278,  DOI: 10.1021/bk-1996-0639.ch019
    219. 219
      (a) Bender, D. M.; Bao, J.; Dantzig, A. H.; Diseroad, W. D.; Law, K. L.; Magnus, N. A.; Peterson, J. A.; Perkins, E. J.; Pu, Y.; Reutzel-Edens, S. M.; Remick, D. M.; Starling, J. J.; Stephenson, G. A.; Vaid, R. K.; Zhang, D.; McCarthy, J. R. Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine. J. Med. Chem. 2009, 52, 69586961,  DOI: 10.1021/jm901181h .
      (b) Pratt, S. E.; Durland-Busbice, S.; Shepard, R. L.; Heinz-Taheny, K.; Iversen, P. W.; Dantzig, A. H. Human carboxylesterase-2 hydrolyzes the prodrug of gemcitabine (LY2334737) and confers prodrug sensitivity to cancer cells. Clin. Cancer Res. 2013, 19, 11591168,  DOI: 10.1158/1078-0432.CCR-12-1184
    220. 220
      (a) Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, H. M.; Steuer, M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J. Med. Chem. 2010, 53, 72027218,  DOI: 10.1021/jm100863x .
      (b) Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A. M.; Otto, M. J.; Sofia, M. J.; Furman, P. A. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem. 2010, 285, 3433734347,  DOI: 10.1074/jbc.M110.161802
    221. 221
      (a) Kawaguchi, T.; Fukushima, S.; Ohmura, M.; Mishima, M.; Nakano, M. Enzymatic and chemical stability of 2′,3′-dideoxy-2′,3′-didehydropyrimidine nucleosides: potential anti-acquired immunodeficiency syndrome agents. Chem. Pharm. Bull. 1989, 37, 19441945,  DOI: 10.1248/cpb.37.1944 .
      (b) Shi, J.; Ray, A. S.; Mathew, J. S.; Anderson, K. S.; Chu, C. K.; Schinazi, R. F. 2,3-Didehydro-2,3-dideoxynucleosides are degraded to furfuryl alcohol under acidic conditions. Bioorg. Med. Chem. Lett. 2004, 14, 21592162,  DOI: 10.1016/j.bmcl.2004.02.031
    222. 222
      Ray, A. S.; Hernandez-Santiago, B. I.; Mathew, J. S.; Murakami, E.; Bozeman, C.; Xie, M.-Y.; Dutschman, G. E.; Gullen, E.; Yang, Z.; Hurwitz, S.; Cheng, Y.-C.; Chu, C. K.; McClure, H.; Schinazi, R. F.; Anderson, K. S. Mechanism of anti-human immunodeficiency virus activity of β-d-6-cyclopropylamino-2′,3′-didehydro-2′,3′-dideoxyguanosine. Antimicrob. Agents Chemother. 2005, 49, 19942001,  DOI: 10.1128/AAC.49.5.1994-2001.2005
    223. 223
      (a) Rana, K. Z.; Dudley, M. N. Clinical pharmacokinetics of stavudine. Clin. Pharmacokinet. 1997, 33, 276284,  DOI: 10.2165/00003088-199733040-00003 .
      (b) Becher, F.; Landman, R.; Mboup, S.; Kane, C. N.; Canestri, A.; Liegeois, F.; Vray, M.; Prevot, M. H.; Leleu, G.; Benech, H. Monitoring of didanosine and stavudine intracellular trisphosphorylated anabolite concentrations in HIV-infected patients. AIDS 2004, 18, 181187,  DOI: 10.1097/00002030-200401230-00006
    224. 224
      (a) Schaeffer, H. J.; Beauchamp, L.; Miranda, de P.; Elion, G. B.; Bauer, D. J.; Collins, P. 9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group. Nature 1978, 272, 583585,  DOI: 10.1038/272583a0 .
      (b) Faulds, D.; Heel, R. C. Ganciclovir, A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs 1990, 39, 597638,  DOI: 10.2165/00003495-199039040-00008
    225. 225
      (a) Soul-Lawton, J.; Seaber, E.; On, N.; Wootton, R.; Rolan, P.; Posner, J. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob. Agents Chemother. 1995, 39, 27592764,  DOI: 10.1128/AAC.39.12.2759 .
      (b) Abete, J. F.; Martín-Davila, P.; Moreno, S.; Quijino, Y.; Vicente, E.; Pou, L. Pharmacokinetics of oral valganciclovir and intravenous ganciclovir administered to prevent cytomegalovirus disease in an adult patient receiving small-intestine transplantation. Antimicrob. Agents Chemother. 2004, 48, 27822783,  DOI: 10.1128/AAC.48.7.2782-2783.2004
    226. 226
      (a) de Vrueh, R. L. A.; Smith, P. L.; Lee, C. P. Transport of L-valine-acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2. J. Pharmacol. Exp. Ther. 1998, 286, 11661170.
      (b) Han, H. K.; de Vrueh, R. L. A.; Rhie, J. K.; Covitz, K. M. Y.; Smith, P. L.; Lee, C. P.; Oh, D. M.; Sadee, W.; Amidon, G. L. 5′-Amino acid esters of antiviral nucleosides, acyclovir and AZT, are absorbed by the intestinal PEPT1 peptide transporter. Pharm. Res. 1998, 15, 11541159,  DOI: 10.1023/A:1011919319810 .
      (c) Sugawara, M.; Huang, W.; Fei, Y. J.; Leibach, F. H.; Ganapathy, V.; Ganapathy, M. E. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J. Pharm. Sci. 2000, 89, 781789,  DOI: 10.1002/(SICI)1520-6017(200006)89:6<781::AID-JPS10>3.0.CO;2-7
    227. 227
      (a) Bonvicini, P.; Levi, A.; Lucchini, V.; Modena, G.; Scorrano, G. Acid-base behavior of alkyl sulfur and oxygen bases. J. Am. Chem. Soc. 1973, 95, 59605964,  DOI: 10.1021/ja00799a023 .
      (b) Fife, T. H.; Jao, L. K. The acid-catalyzed hydrolysis of 2-(substituted phenyl)-1,3-oxathiolanes. J. Am. Chem. Soc. 1969, 91, 42174220,  DOI: 10.1021/ja01043a034
    228. 228
      Chandrasekhar, S.; Chopra, D.; Gopalaiah, K.; Row, T. The generalized anomeric effect in the 1,3-thiazolidines: Evidence for both sulphur and nitrogen as electron donors. Crystal structures of various N-acylthiazolidines including mercury(II) complexes. Possible relevance to penicillin action. J. Mol. Struct. 2007, 837, 118131,  DOI: 10.1016/j.molstruc.2006.10.034
    229. 229
      Dionne, G. 3TC: a Canadian scientific success story. McGill Journal of Medicine (MJM). 1999, 5, 6065
    230. 230
      Liotta, D. C.; Painter, G. R. Discovery and development of the anti-human immunodeficiency virus drug, emtricitabine (emtriva, FTC). Acc. Chem. Res. 2016, 49, 20912098,  DOI: 10.1021/acs.accounts.6b00274
    231. 231
      (a) Gumina, G.; Song, G.; Chu, C. K. L-Nucleosides as chemotherapeutic agents. FEMS Microbiol. Lett. 2001, 202, 915,  DOI: 10.1016/S0378-1097(01)00285-3 .
      (b) Kim, H. O.; Shanmuganatban, K.; Alves, A. J.; Jeong, L. S.; Beacb, J. W.; Schinazi, R. F.; Chang, C.; Cheng, Y.; Chu, C. K. Potent anti-HIV and anti-HBV activities of (−)-L-β-dioxolane-C and (+)-L-β-dioxolane-T and their asymmetric syntheses. Tetrahedron Lett. 1992, 33, 68996902,  DOI: 10.1016/S0040-4039(00)60890-0
    232. 232
      (a) Grove, K. L.; Guo, X.; Liu, S.-H.; Gao, Z.; Chu, C. K.; Cheng, Y.-C. Anticancer activity of β-l-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration. Cancer Res. 1995, 55, 30083011.
      (b) Lapointe, R.; Letourneau, R.; Steward, W.; Hawkins, R. E.; Batist, G.; Vincent, M.; Whittom, R.; Eatock, M.; Jolivet, J.; Moore, M. Phase II study of troxacitabine in chemotherapy-naïve patients with advanced cancer of the pancreas. Annals Oncol. 2005, 16, 289293,  DOI: 10.1093/annonc/mdi061 .
      (c) Moore, L. E.; Boudinot, F. D.; Chu, C. K. Preclinical pharmacokinetics of β-L-dioxolane-cytidine, a novel anticancer agent, in rats. Cancer Chemother. Pharmacol. 1997, 39, 532536,  DOI: 10.1007/s002800050609 .
      (d) Swords, R.; Giles, F. Troxacitabine in acute leukemia. Hematology 2007, 12, 219227,  DOI: 10.1080/10245330701406881
    233. 233
      Lin, J.; Kira, T.; Gullen, E.; Choi, Y.; Qu, F.; Chu, C. K.; Cheng, Y. Structure-activity relationships of L-dioxolane uracil nucleosides as anti-Epstein Barr virus agents. J. Med. Chem. 1999, 42, 22122217,  DOI: 10.1021/jm9806749
    234. 234
      Liang, C.; Lee, D. W.; Newton, M. G.; Chu, C. K. Synthesis of L-dioxolane nucleosides and related chemistry. J. Org. Chem. 1995, 60, 15461553,  DOI: 10.1021/jo00111a012
    235. 235
      (a) Goodwin, N. C.; Mabon, R.; Harrison, B. A.; Shadoan, M. K.; Almstead, Z. Y.; Xie, Y.; Healy, J.; Buhring, L. M.; DaCosta, C. M.; Bardenhagen, J.; Mseeh, F.; Liu, Q.; Nouraldeen, A.; Wilson, A. G.; Kimball, D.; Powell, D. R.; Rawlins, D. B. Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes. J. Med. Chem. 2009, 52, 62016204,  DOI: 10.1021/jm900951n .
      (b) Goodwin, N. C.; Ding, Z.; Harrison, B. A.; Strobel, E. D.; Harris, A. L.; Smith, M.; Thompson, A. Y.; Xiong, W.; Mseeh, F.; Bruce, D. J.; Diaz, D.; Gopinathan, S.; Li, L.; O’Neill, E.; Thiel, M.; Wilson, A. G.; Carson, K. G.; Powell, D. R.; Rawlins, D. B. Discovery of LX2761, a sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor restricted to the intestinal lumen, for the treatment of diabetes. J. Med. Chem. 2017, 60, 710721,  DOI: 10.1021/acs.jmedchem.6b01541
    236. 236
      Fioretto, P.; Zambon, A.; Rossato, M.; Busetto, L.; Vettor, R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care 2016, 39, S165S171,  DOI: 10.2337/dcS15-3006
    237. 237
      (a) Selnick, H. G.; Hess, J. F.; Tang, C.; Liu, K.; Schachter, J. B.; Ballard, J. E.; Marcus, J.; Klein, D. J.; Wang, X.; Pearson, M.; Savage, M. J.; Kaul, R.; Li, T.-S.; Vocadlo, D. J.; Zhou, Y.; Zhu, Y.; Mu, C.; Wang, Y.; Wei, Z.; Bai, C.; Duffy, J. L.; McEachern, E. J. Discovery of MK-8719, a potent O-GlcNAcase inhibitor as a potential treatment for tauopathies. J. Med. Chem. 2019, 62, 1006210097,  DOI: 10.1021/acs.jmedchem.9b01090 .
      (b) Wang, X.; Li, W.; Marcus, J.; Pearson, M.; Song, L.; Smith, K.; Terracina, G.; Lee, J.; Hong, K. K.; Lu, S. X.; Hyde, L.; Chen, S. C.; Kinsley, D.; Melchor, J. P.; Rubins, D. J.; Meng, X.; Hostetler, E.; Sur, C.; Zhang, L.; Schachter, J. B.; Hess, J. F.; Senick, H. G.; Vocadlo, D. J.; McEachern, E. J.; Uslaner, J. M.; Duffy, J. L.; Smith, S. M. MK-8719, a novel and selective O-GlcNAcase inhibitor that reduces the formation of pathological tau and ameliorates neurodegeneration in a mouse model of tauopathy. J. Pharmacol. Exp. Ther. 2020, 374, 252263,  DOI: 10.1124/jpet.120.266122
    238. 238
      Passioura, T.; Watashi, K.; Fukano, K.; Shimura, S.; Saso, W.; Morishita, R.; Ogasawara, Y.; Tanaka, Y.; Mizokami, M.; Sureau, C.; Suga, H.; Wakita, T. De novo macrocyclic peptide inhibitors of hepatitis B virus cellular entry. Cell Chem. Biol. 2018, 25, 906915,  DOI: 10.1016/j.chembiol.2018.04.011
    239. 239
      Liu, Y.; Ruan, H.; Li, Y.; Sun, G.; Liu, X.; He, W.; Mao, F.; He, M.; Yan, L.; Zhong, G.; Yan, H.; Li, W.; Zhang, Z. Potent and specific inhibition of NTCP-mediated HBV/HDV infection and substrate transporting by a novel, oral-available cyclosporine a analogue. J. Med. Chem. 2021, 64, 543565,  DOI: 10.1021/acs.jmedchem.0c01484
    240. 240
      (a) Satchell, D. P. N.; Satchell, R. S. Mechanisms of hydrolysis of thioacetals. Chem. Soc. Rev. 1990, 19, 5581,  DOI: 10.1039/cs9901900055 .
      (b) Ali, M.; Satchell, D. P. N. Kinetics and mechanism of hydrolysis of open-chain thioacetals derived from benzophenone and the reactivity of α-thiophenyl carbocations. J. Chem. Soc., Perkin Trans. 2 1995, 167170,  DOI: 10.1039/P29950000167
    241. 241
      Burghardt, T. E. Developments in the deprotection of thioacetals. J. Sulfur Chem. 2005, 26, 411427,  DOI: 10.1080/17415990500195198
    242. 242
      Cushman, D. W.; Ondetti, M. A. Personal and historical perspectives. History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension 1991, 17, 589592,  DOI: 10.1161/01.HYP.17.4.589
    243. 243
      Patchett, A. A. Excursions in drug discovery. J. Med. Chem. 1993, 36, 20512058,  DOI: 10.1021/jm00067a001
    244. 244
      Smith, E. M.; Swiss, G. F.; Neustadt, B. R.; McNamara, P.; Gold, E. H.; Sybertz, E. J.; Baum, T. Angiotensin converting enzyme inhibitors: spirapril and related compounds. J. Med. Chem. 1989, 32, 16001606,  DOI: 10.1021/jm00127a033
    245. 245
      Noble, S.; Sorkin, E. M. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension. Drugs 1995, 49, 750766,  DOI: 10.2165/00003495-199549050-00008
    246. 246
      Sybertz, E. J.; Watkins, R. W.; Ahn, H. S.; Baum, T.; La Rocca, P.; Patrick, J.; Leitz, F. Pharmacologic, metabolic, and toxicologic profile of spirapril (SCH 33844), a new angiotensin converting inhibitor. J. Cardiovasc. Pharmacol. 1987, 10, S105S108,  DOI: 10.1097/00005344-198706107-00020
    247. 247
      Guitard, C.; Lohmann, F. W.; Alfiero, R.; Ruina, M.; Alvisi, V. Cardiovasc. Drugs Ther. 1997, 11, 449457,  DOI: 10.1023/A:1007797405850
    248. 248
      (a) Yamashita, S.; Matsuzawa, Y. Where are we with probucol: a new life for an old drug?. Atherosclerosis 2009, 207, 1623,  DOI: 10.1016/j.atherosclerosis.2009.04.002 .
      (b) Buckley, M. M.-T.; Goa, K. L.; Price, A. H.; Brogden, R. N. A reappraisal of its pharmacological properties and therapeutic use in hypercholesterolaemia. Drugs 1989, 37, 761800,  DOI: 10.2165/00003495-198937060-00002
    249. 249
      (a) Neuworth, M. B.; Laufer, R. J.; Barnhart, J. W.; Sefranka, J. A.; McIntosh, D. D. Synthesis and hypocholesterolemic activity of alkylidenedithio bisphenols. J. Med. Chem. 1970, 13, 722725,  DOI: 10.1021/jm00298a031 .
      (b) Carew, T. E.; Schwenke, D. C.; Steinberg, D. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: Evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc. Natl. Acad. Sci. U. S. A. 1987, 84, 77257729,  DOI: 10.1073/pnas.84.21.7725
    250. 250
      Meng, C. Q.; Somers, P. K.; Hoong, L. K.; Zheng, X. S.; Ye, Z.; Worsencroft, K. J.; Simpson, J. E.; Hotema, M. R.; Weingarten, M. D.; MacDonald, M. L.; Hill, R. R.; Marino, E. M.; Suen, K.-L.; Luchoomun, J.; Kunsch, C.; Landers, L. K.; Stefanopoulos, D.; Howard, R. B.; Sundell, C. L.; Saxena, U.; Wasserman, M. A.; Sikorski, J. A. Discovery of novel phenolic antioxidants as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases. J. Med. Chem. 2004, 47, 64206432,  DOI: 10.1021/jm049685u
    251. 251
      (a) Meng, C. Q.; Somers, P. K.; Rachita, C. L.; Holt, L. A.; Hoong, L. K.; Zheng, X. S.; Simpson, J. E.; Hill, R. R.; Olliff, L. K.; Kunsch, C. K.; Sundell, C. L.; Parthasarathy, S.; Saxena, U.; Sikorski, J. A.; Wasserman, M. A. Novel phenolic antioxidants as multifunctional inhibitors of inducible VCAM-1 expression for use in atherosclerosis. Bioorg. Med. Chem. Lett. 2002, 12, 25452548,  DOI: 10.1016/S0960-894X(02)00516-4 .
      (b) Muldrew, K. M.; Franks, A. M. Succinobucol: review of the metabolic, antiplatelet and cardiovascular effects. Expert Opin. Invest. Drugs 2009, 18, 531539,  DOI: 10.1517/13543780902849244
    252. 252
      (a) Groso, G.; Caputo, O.; Ceruti, M.; Biglino, G.; Franzone, J. S.; Cirillo, R. Synthesis and antibronchospastic activity of theophylline thioacetal derivatives. Eur. J. Med. Chem. 1989, 24, 635638,  DOI: 10.1016/0223-5234(89)90035-4 .
      (b) Franzone, J. S.; Reboani, M. C.; Biglione, V.; Cirillo, R. Pharmacological and toxicological activities of a new methylxanthine derivative [7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine] with antibronchospastic and mucoregulatory properties. Drugs Exp. Clin. Res. 1990, 16, 263276.
      (c) Reboani, M. C.; Franzone, J. S. In vivo anti-inflammatory activity of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine. Drugs Exp. Clin. Res. 1990, 16, 277284.
      (d) Cravanzola, C.; Grosa, G.; Franzone, J. S. Kinetic and metabolic studies of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine in the rat. Drugs Exp. Clin. Res. 1990, 16, 285291.
      (e) Grosa, G.; Caputo, O.; Ceruti, M.; Biglino, G.; Franzone, J. S.; Cravanzola, C. Metabolism of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine by rat liver microsomes. Diastereoselective metabolism of the 1,3-dithiolane ring. Drug Metab. Dispos. 1991, 19, 454457.
      (f) Auret, B. J.; Boyd, D. R.; Dunlop, R.; Drake, A. F. Stereoselectivity during fungal sulphoxidations of 1,3-dithiolanes. J. Chem. Soc., Perkin Trans. 1 1988, 28272829,  DOI: 10.1039/p19880002827
    253. 253
      Fulop, F.; Mattinen, J.; Pihlaja, R. Ring-chain tautomerism in 1,2-thiazolidines. Tetrahedron 1990, 46, 65456552,  DOI: 10.1016/S0040-4020(01)96019-3
    254. 254
      Singh, G. S. β-lactams in the new millennium. Part-II: Cephems, oxacephems, penams and sulbactam. Mini-Rev. Med. Chem. 2004, 4, 93109,  DOI: 10.2174/1389557043487547
    255. 255
      Bush, K.; Bradford, P. A. β-Lactams and β-lactamase inhibitors: an overview. Cold Spring Harbor Perspect. Med. 2016, 6, a025247  DOI: 10.1101/cshperspect.a025247
    256. 256
      Szultka, M.; Krzeminski, R.; Jackowski, M.; Buszewski, B. Identification of in vitro metabolites of amoxicillin in human liver microsomes by LC-ESI/MS. Chromatographia 2014, 77, 10271035,  DOI: 10.1007/s10337-014-2648-2
    257. 257
      Smith, P. W.; Zuccotto, F.; Bates, R. H.; Martinez-Martinez, M. S.; Read, K. D.; Peet, C.; Epemolu, O. Pharmacokinetics of β-lactam antibiotics: clues from the past to help discover long-acting oral drugs in the future. ACS Infect. Dis. 2018, 4, 14391447,  DOI: 10.1021/acsinfecdis.8b00160
    258. 258
      (a) Drawz, S. M.; Bonomo, R. A. Three decades of β-lactamase inhibitors. Clin. Microbiol. Rev. 2010, 23, 160201,  DOI: 10.1128/CMR.00037-09 .
      (b) Gonzalez-Bello, C.; Rodríguez, D.; Pernas, M.; Rodríguez, A.; Colchon, E. β-Lactamase inhibitors to restore the efficacy of antibiotics against superbugs. J. Med. Chem. 2020, 63, 18591881,  DOI: 10.1021/acs.jmedchem.9b01279
    259. 259
      English, A. R.; Retsema, J. A.; Girard, A. E.; Lynch, J. E.; Barth, W. E. CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterization. Antimicrob. Agents Chemother. 1978, 14, 414419,  DOI: 10.1128/AAC.14.3.414
    260. 260
      English, A. R.; Retsema, J. A.; Girard, A. E.; Lynch, J. E.; Barth, W. E. CP-45,899, a β-lactamase inhibitor that extends the antibacterial spectrum of β-lactams: initial bacteriological characterization. Antimicrob. Agents Chemother. 1978, 14, 414419,  DOI: 10.1128/AAC.14.3.414
    261. 261
      Papp-Wallace, K. M.; Bethel, C. R.; Caillon, J.; Barnes, M. D.; Potel, G.; Bajaksouzian, S.; Rutter, J. D.; Reghal, A.; Shapiro, S.; Taracila, M. A.; Jacobs, M. R.; Bonomo, R. A.; Jacqueline, C. Beyond piperacillin-tazobactam: cefepime and AAI101 as a potent β-lactam-β-lactamase inhibitor combination. Antimicrob. Agents Chemother. 2019, 63, e00105  DOI: 10.1128/AAC.00105-19
    262. 262
      Chen, Y. L.; Chang, C. W.; Hedberg, K. Synthesis of a potent β-lactamase inhibitor-1,1-dioxo-6-(2-pyridyl)methylenepenicillanic acid and its reaction with sodium methoxide. Tetrahedron Lett. 1986, 27, 34493452,  DOI: 10.1016/S0040-4039(00)84819-4
    263. 263
      (a) Vazquez-Ucha, J. C.; Maneiro, M.; Martinez-Guitian, M.; Buynak, J.; Bethel, C. R.; Bonomo, R. A.; Bou, G.; Poza, M.; Gonzalez-Bello, C.; Beceiro, A. Activity of the β-lactamase inhibitor LN-1–255 against carbapenem-hydrolyzing class D β-lactamases from Acinetobacter baumannii. Antimicrob. Agents Chemother. 2017, 61, e01172–17  DOI: 10.1128/AAC.01172-17 .
      (b) Vázquez-Ucha, J. C.; Martínez-Guitián, M.; Maneiro, M.; Conde-Perez, K.; Álvarez-Fraga, L.; Torrens, G.; Oliver, A.; Buynak, J. D.; Bonomo, R. A.; Bou, G.; González-Bello, C.; Poza, M.; Beceiro, A. Therapeutic efficacy of LN-1–255 in combination with imipenem in severe infection caused by carbapenem-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 2019, 63, e01092  DOI: 10.1128/AAC.01092-19
    264. 264
      Lee, M.-H. H.; Graham, G. G.; Williams, K. M.; Day, R. O. A benefit-risk assessment of benzbromarone in the treatment of gout: was its withdrawal from the market in the best interest of patients?. Drug Saf. 2008, 31, 643665,  DOI: 10.2165/00002018-200831080-00002
    265. 265
      (a) Uda, J.; Kobashi, S.; Miyata, S.; Ashizawa, N.; Matsumoto, K.; Iwanaga, T. Discovery of dotinurad (FYU-981), a new phenol derivative with highly potent uric acid lowering activity. ACS Med. Chem. Lett. 2020, 11, 20172023,  DOI: 10.1021/acsmedchemlett.0c00176 .
      (b) Omura, K.; Miyata, K.; Kobashi, S.; Ito, A.; Fushimi, M.; Uda, J.; Sasaki, T.; Iwanaga, T.; Ohashi, T. Ideal pharmacokinetic profile of dotinurad as a selective reabsorption inhibitor. Drug Metab. Pharmacokinet. 2020, 35, 313320,  DOI: 10.1016/j.dmpk.2020.03.002
    266. 266
      Hansen, A. H.; Sergeev, E.; Bolognini, D.; Sprenger, R. R.; Ekberg, J. H.; Ejsing, C. S.; McKenzie, C. J.; Ulven, E. R.; Milligan, G.; Ulven, T. Discovery of a potent thiazolidine free fatty acid receptor 2 agonist with favorable pharmacokinetic properties. J. Med. Chem. 2018, 61, 95349550,  DOI: 10.1021/acs.jmedchem.8b00855
    267. 267
      (a) Edmondson, S. D.; Mastracchio, A.; Beconi, M.; Colwell, L. F.; Habulihaz, B.; He, H.; Kumar, S.; Leiting, B.; Lyons, K. A.; Mao, A.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Zhu, L.; Thornberry, N.; Weber, A.; Parmee, E. R. Potent and selective proline derived dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 51515155,  DOI: 10.1016/j.bmcl.2004.07.056 .
      (b) Park, W. S.; Kang, S. K.; Jun, M. A.; Shin, M. S.; Kim, K. Y.; Rhee, S. D.; Bae, M. A.; Kim, M. S.; Kim, K. R.; Kang, N. S.; Yoo, S.; Lee, J. O.; Song, D. Y.; Silinski, P.; Schneider, S. E.; Ahn, J. H.; Kim, S. S. Discovery of β-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 13661370,  DOI: 10.1016/j.bmcl.2011.01.041
    268. 268
      Carzaniga, L.; Amari, G.; Rizzi, A.; Capaldi, C.; Fanti, R. D.; Ghidini, E.; Villetti, G.; Carnini, C.; Moretto, N.; Facchinetti, F.; Caruso, P.; Marchini, G.; Battipaglia, L.; Patacchini, R.; Cenacchi, V.; Volta, R.; Amadei, F.; Pappani, A.; Capacchi, S.; Bagnacani, V.; Delcanale, M.; Puccini, P.; Catinella, S.; Civelli, M.; Armani, E. Discovery and optimization of thiazolidinyl and pyrrolidinyl derivatives as Inhaled PDE4 inhibitors for respiratory diseases. J. Med. Chem. 2017, 60, 1002610046,  DOI: 10.1021/acs.jmedchem.7b01044
    269. 269
      Chen, T.; Reich, N. W.; Bell, N.; Finn, P. D.; Rodriguez, D.; Kohler, J.; Kozuka, K.; He, L.; Spencer, A. G.; Charmot, D.; Navre, M.; Carreras, C. W.; Koo-McCoy, S.; Tabora, J.; Caldwell, J. S.; Jacobs, J. W.; Lewis, J. G. Design of gut-restricted thiazolidine agonists of G protein-coupled bile acid receptor 1 (GPBAR1, TGR5). J. Med. Chem. 2018, 61, 75897613,  DOI: 10.1021/acs.jmedchem.8b00308
    270. 270
      Tobias, P. S.; Kallen, R. G. Kinetics and equilibriums of the reaction of pyridoxal 5′-phosphate with ethylenediamine to form Schiff bases and cyclic geminal diamines. Evidence for kinetically competent geminal diamine intermediates in transimination sequences. J. Am. Chem. Soc. 1975, 97, 65306539,  DOI: 10.1021/ja00855a041
    271. 271
      Faine, S.; Harper, M. Independent antibiotic actions of hetacillin and ampicillin revealed by fast methods. Antimicrob. Agents Chemother. 1973, 3, 1518,  DOI: 10.1128/AAC.3.1.15
    272. 272
      (a) Balkovec, J. M.; Hughes, D. L.; Masurekar, P. S.; Sable, C. A.; Schwartz, R. E.; Singh, S. B. Discovery and development of first in class antifungal caspofungin (CANCIDAS®) - a case study. Nat. Prod. Rep. 2014, 31, 1534,  DOI: 10.1039/C3NP70070D .
      (b) Bouffard, F. A.; Hammond, M. L.; Arison, B. H. Pneumocandin Bo acid degradate. Tetrahedron Lett. 1995, 36, 14051408,  DOI: 10.1016/0040-4039(95)00017-7
    273. 273
      Kurtz, M. B.; Douglas, C.; Marrinan, J.; Nollstadt, K.; Onishi, J.; Dreikorn, S.; Milligan, J.; Mandala, S.; Thompson, J.; Balkovec, J. M. Increased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis. Antimicrob. Agents Chemother. 1994, 38, 27502757,  DOI: 10.1128/AAC.38.12.2750
    274. 274
      (a) Bartizal, K.; Gill, C. J.; Abruzzo, G. K.; Flattery, A. M.; Kong, L.; Scott, P. M.; Smith, J. G.; Leighton, C. E.; Bouffard, A.; Dropinski, J. F.; Balkovec, J. In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872). Antimicrob. Agents Chemother. 1997, 41, 23262332,  DOI: 10.1128/AAC.41.11.2326 .
      (b) Hajdu, R.; Thompson, R.; Sundelof, J. G.; Pelak, B. A.; Bouffard, F. A.; Dropinski, J. F.; Kropp, H. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872). Antimicrob. Agents Chemother. 1997, 41, 23392344,  DOI: 10.1128/AAC.41.11.2339
    275. 275
      (a) Snyder, L. B.; Meng, Z.; Mate, R.; D’Andrea, S. V.; Marinier, A.; Quesnelle, C. A.; Gill, P.; DenBleyker, K. L.; Fung-Tomc, J. C.; Frosco, M.; Martel, A.; Barrett, J. F.; Bronson, J. J. Discovery of isoxazolinone antibacterial agents. Nitrogen as a replacement for the stereogenic center found in oxazolidinone antibacterials. Bioorg. Med. Chem. Lett. 2004, 14, 47354739,  DOI: 10.1016/j.bmcl.2004.06.076 .
      (b) Quesnelle, C. A.; Gill, P.; Roy, S.; Dodier, M.; Marinier, A.; Martel, A.; Snyder, L. B.; D’Andrea, S. V.; Bronson, J. J.; Frosco, M.; Beaulieu, D.; Warr, G. A.; DenBleyker, K. L.; Stickle, T. M.; Yang, H.; Chaniewski, S. E.; Ferraro, C. A.; Taylor, D.; Russell, J. W.; Santone, K. S.; Clarke, J.; Drain, R. L.; Knipe, J. O.; Mosure, K.; Barrett, J. F. Biaryl isoxazolinone antibacterial agents. Bioorg. Med. Chem. Lett. 2005, 15, 27282733,  DOI: 10.1016/j.bmcl.2005.04.003
    276. 276
      Kees, K. L.; Caggiano, T. J.; Steiner, K. E.; Fitzgerald, J. J., Jr.; Kates, M. J.; Christos, T. E.; Kulishoff, J. M., Jr.; Moore, R. D.; McCaleb, M. L. Studies on new acidic azoles as glucose-lowering agents in obese, diabetic db/db mice. J. Med. Chem. 1995, 38, 617628,  DOI: 10.1021/jm00004a008
    277. 277
      (a) Noshi, T.; Kitano, M.; Taniguchi, K.; Yamamoto, A.; Omoto, S.; Baba, K.; Hashimoto, T.; Ishida, K.; Kushima, Y.; Hattori, K.; Kawai, M.; Yoshida, R.; Kobayashi, M.; Yoshinaga, T.; Sato, A.; Okamatsu, M.; Sakoda, Y.; Kida, H.; Shishido, T.; Naito, A. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res. 2018, 160, 109117,  DOI: 10.1016/j.antiviral.2018.10.008 .
      (b) Miyagawa, M.; Akiyama, T.; Taoda, Y.; Takaya, K.; Takahashi-Kageyama, C.; Tomita, K.; Yasuo, K.; Hattori, K.; Shano, S.; Yoshida, R.; Shishido, T.; Yoshinaga, T.; Sato, A.; Kawai, M. Synthesis and SAR study of carbamoyl pyridone bicyclederivatives as potent inhibitors of influenza cap-dependent endonuclease. J. Med. Chem. 2019, 62, 81018114,  DOI: 10.1021/acs.jmedchem.9b00861
    278. 278
      Taoda, Y.; Miyagawa, M.; Akiyama, T.; Tomita, K.; Hasegawa, Y.; Yoshida, R.; Noshi, T.; Shishido, T.; Kawai, M. Dihydrodibenzothiepine: promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitor. Bioorg. Med. Chem. Lett. 2020, 30, 127547,  DOI: 10.1016/j.bmcl.2020.127547
    279. 279
      (a) Heo, Y.-A. Baloxavir: first global approval. Drugs 2018, 78, 693697,  DOI: 10.1007/s40265-018-0899-1 .
      (b) Shirley, M. Baloxavir marboxil: a review in acute uncomplicated influenza. Drugs 2020, 80, 11091118,  DOI: 10.1007/s40265-020-01350-8
    280. 280
      Raheem, I. T.; Walji, A. M.; Klein, D.; Sanders, J. M.; Powell, D. A.; Abeywickrema, P.; Barbe, G.; Bennet, A.; Clas, S.; Dubost, D.; Embrey, M.; Grobler, J.; Hafey, M. J.; Hartingh, T. J.; Hazuda, D. J.; Miller, M. D.; Moore, K. P.; Pajkovic, N.; Patel, S.; Rada, V.; Rearden, P.; Schreier, J. D.; Sisko, J.; Steele, T. G.; Truchon, J.; Wai, J.; Xu, M.; Coleman, P. J. Discovery of 2-pyridinone aminals: a prodrug strategy to advance a second generation of HIV-1 integrase strand transfer inhibitors. J. Med. Chem. 2015, 58, 81548165,  DOI: 10.1021/acs.jmedchem.5b01037
    281. 281
      Reich, S. H.; Sprengeler, P. A.; Chiang, G. G.; Appleman, J. R.; Chen, J.; Clarine, J.; Eam, B.; Ernst, J. T.; Han, Q.; Goel, V. K.; Han, E.; Huang, V.; Hung, I.; Jemison, A.; Jessen, K. A.; Molter, J.; Murphy, D.; Neal, M.; Parker, G. S.; Shaghafi, M.; Sperry, S.; Staunton, J.; Stumpf, C. R.; Thompson, P. A.; Tran, C.; Webber, S. E.; Wegerski, C. J.; Zheng, H.; Webster, K. R. Structure-based design of pyridone-aminal eFT508 targeting dysregulated translation by selective mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) inhibition. J. Med. Chem. 2018, 61, 35163540,  DOI: 10.1021/acs.jmedchem.7b01795
    282. 282
      Paulini, R.; Laus Müller, K.; Diederich, F. Orthogonal multipolar interactions in structural chemistry and biology. Angew. Chem., Int. Ed. 2005, 44, 17881805,  DOI: 10.1002/anie.200462213
    283. 283
      A study to evaluate the efficacy and safety of TAK-906 in adult participants with symptomatic idiopathic or diabetic gastroparesis. https://clinicaltrials.gov/ct2/show/NCT03544229 (accessed April 29, 2021).
    284. 284
      Whiting, R. L.; Darpo, B.; Chen, C.; Fletcher, M.; Combs, D.; Xue, H.; Stoltz, R. R. Safety, pharmacokinetics, and pharmacodynamics of trazpiroben (TAK-906), a novel selective D2/D3 receptor antagonist: a Phase 1 randomized, placebo-controlled single- and multiple-dose escalation study in healthy participants. Clin. Pharmacol. Drug Dev. 2021, in press.  DOI: 10.1002/cpdd.906 . Epub ahead of print. PMID: 33462988.
    285. 285
      A study to evaluate the safety and efficacy of NG101 in adult participants with symptomatic diabetic or idiopathic gastroparesis. https://clinicaltrials.gov/ct2/show/NCT04303195 (accessed April 29, 2021).
    286. 286
      Nishihara, M.; Ramsden, D.; Balani, S. K. Evaluation of the drug-drug interaction potential for trazpiroben (TAK-906), a D2/D3 receptor antagonist for gastroparesis, towards cytochrome P450s and transporters. Xenobiotica 2021 in press. 51 668 DOI: 10.1080/00498254.2021.1912438 .
    287. 287
      (a) Bond, S.; Draffan, A. G.; Fenner, J. E.; Lambert, J.; Lim, C. Y.; Lin, B.; Luttick, A.; Mitchell, J. P.; Morton, C. J.; Nearn, R. H.; Sanford, V.; Stanislawski, P. C.; Tucker, S. P. The discovery of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 1. Bioorg. Med. Chem. Lett. 2015, 25, 969975,  DOI: 10.1016/j.bmcl.2014.11.018 .
      (b) Bond, S.; Draffan, A. G.; Fenner, J. E.; Lambert, J.; Lim, C. Y.; Lin, B.; Luttick, A.; Mitchell, J. P.; Morton, C. J.; Nearn, R. H.; Sanford, V.; Anderson, K. H.; Mayes, P. A.; Tucker, S. P. 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 2: Identification of BTA9881 as a preclinical candidate. Bioorg. Med. Chem. Lett. 2015, 25, 976981,  DOI: 10.1016/j.bmcl.2014.11.024
    288. 288
      Gentry, P. R.; Kokubo, M.; Bridges, T. M.; Kett, N. R.; Harp, J. M.; Cho, H. P.; Smith, E.; Chase, P.; Hodder, P. S.; Niswender, C. M.; Daniels, J. S.; Conn, P. J.; Wood, M. R.; Lindsley, C. M. Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). J. Med. Chem. 2013, 56, 93519355,  DOI: 10.1021/jm4013246

    Cited By


    This article has not yet been cited by other publications.

    • Abstract

      Figure 1

      Figure 1. Structural elements with two heteroatoms, either oxygen, nitrogen, or sulfur or combinations thereof bound to a single sp3 carbon atom that have been exploited in drug design.

      Figure 2

      Figure 2. Naturally occurring polymers with nucleic acid oligomers and polysaccharides dependent upon geminal diheteroatomic linkages (marked in red), while polypeptides rely upon amide bonds for concatenation.

      Figure 3

      Figure 3. Select naturally occurring compounds 119 that incorporate geminal diheteroatomic motifs, which are marked in red.

      Figure 4

      Figure 4. Geminal diheteroatomic motifs that are present in marketed oral drugs, which are highlighted in red.

      Scheme 1

      Scheme 1. Mechanism of Hydrolysis of Ketals and Acetals

      Scheme 2

      Scheme 2. Metabolism of Doxofylline (64)

      Scheme 3

      Scheme 3. Metabolism of the Benzodioxole Moiety Leading to CYP Enzyme Inhibition and the Production of Catechol and ortho-Quinone

      Scheme 4

      Scheme 4. Potential Pathway for the Acid-Catalyzed Degradation of [1,3]Dioxolo[4,5-c]pyridine 100

      Scheme 5

      Scheme 5. Condensation of an Amino Acid-Derived Aldehyde 119 with a Tartaric Acid 120 to Afford 3-Aza-6,8-dioxabicyclo[3.2.1]octanes 121 and Their Reduction to Amines 122

      Scheme 6

      Scheme 6. Structure of 133 and Its Chemical Degradation and Metabolic Pathways

      Scheme 7

      Scheme 7. Structure of 143, Its Evolution to 144 and 90, and Metabolism of 144

      Scheme 8

      Scheme 8. Metabolism of 150 to Afford 160

      Scheme 9

      Scheme 9. Metabolism of Phlorizin (172) to Phloretin (173) in Vivo

      Scheme 10

      Scheme 10. Metabolism of 174 to the Glucoside 175 in Vivo

      Scheme 11

      Scheme 11. Proposed Mechanism for the Hydrolysis of 188 at High pH Values

      Scheme 12

      Scheme 12. Potential Hydrolytic Degradation Pathways for 197

      Scheme 13

      Scheme 13. Metabolic Pathways for 202

      Scheme 14

      Scheme 14. Acid-Mediated Degradation of 169

      Figure 5

      Figure 5. A. Key H-bonding interactions between 21 and the NK1 receptor. B. Conformation of 21 bound to the NK1 receptor. C. Single-crystal X-ray structure of 21 (GOPDUK, deposition number 117932 in the CSD).(114c,d)

      Figure 6

      Figure 6. Single-crystal X-ray structure of 218 (QESQIR, deposition number 1817710 in the CSD).(116d)

      Figure 7

      Figure 7. Conformation of 226 when bound to BACE1 (Protein Data Bank 6BFX).(118)

      Figure 8

      Figure 8. 1H NMR data for the substituted dioxanes 281a/b.

      Scheme 15

      Scheme 15. Acid-Catalyzed Degradation of 282 to afford 285 and the N-Dealkylation Metabolic Pathway Observed in Rats and Dogs to Afford 286 and 287

      Figure 9

      Figure 9. Design principles that led to the discovery of 290.

      Figure 10

      Figure 10. Structure of the 5-LO inhibitor 295, metabolic pathways and structural evolution.

      Figure 11

      Figure 11. Design principle subtending the discovery of the core bicyclic ring system found in tofogliflozin (314).

      Figure 12

      Figure 12. Conformations available to 1,7-dioxaspiro[5.5]undecane (315).

      Figure 13

      Figure 13. Structure of HIV-1 protease inhibitor 321 depicting key intermolecular H-bonding interactions and evolution to bicyclic ethers.

      Figure 14

      Figure 14. Depiction of the anomeric effect in 195.

      Scheme 16

      Scheme 16. Potential Modes of Action of 195 Relying upon Iron-Catalyzed Degradation to Oxygen- or Carbon-Based Radicals

      Figure 15

      Figure 15. Depiction of the anomeric effects in 1,2,4-trioxolane 365, 1,2,4-troxane 361, and tetraoxane 366.

      Scheme 17

      Scheme 17. Degradation of 372373 and Aldehyde 374

      Scheme 18

      Scheme 18. Mechanism of Acid-Catalyzed (N,O)-Aminal Hydrolysis

      Figure 16

      Figure 16. Structures and chemical stability under acidic conditions of pseudoproline derivatives.

      Figure 17

      Figure 17. Structures and evolution of HCV NS5A inhibitors.

      Scheme 19

      Scheme 19. Proposed Mechanism of Inactivation of Serine-Containing β-Lactamase Enzymes by 393

      Figure 18

      Figure 18. Structures and degradation pathways of 403 and 404.

      Figure 19

      Figure 19. Principle behind the design and synthesis of the HIV-1 integrase inhibitor 407.

      Scheme 20

      Scheme 20. Design of 413 and the Synthetic Approach Developed to Access the Core Molecule 418

      Figure 20

      Figure 20. Design principle behind the discovery of 421.

      Figure 21

      Figure 21. Structure of the carboxonium (carbonylonium) ion intermediate that would be formed if 426 hydrolyzed by loss of the amine substituent.

      Scheme 21

      Scheme 21. Degradation Pathway for 438 Involving the Departure of the Phenol Moiety, A Process That Is Disfavored Electronically and by the Introduction of Strain in the Azetidinone Ring

      Scheme 22

      Scheme 22. A1 Mechanism of Acid-Catalyzed Hydrolysis of Nucleosides

      Scheme 23

      Scheme 23. Degradation and Metabolism of 447

      Scheme 24

      Scheme 24. Intracellular Metabolism of 458

      Scheme 25

      Scheme 25. Hydrolysis of 2′-F-ara-ddI and 2′-F-ara-ddA Disfavored by the Presence of the 2′-F Atom, Which Destabilizes the Oxocarbenium Ion Intermediate

      Scheme 26

      Scheme 26. Metabolism of 466 and 467

      Figure 22

      Figure 22. Evolutionary path from 472477.

      Scheme 27

      Scheme 27. Structure of 480 and Its Intracellular Metabolic Pathway to the Active Triphosphate 482

      Scheme 28

      Scheme 28. Proposed Decomposition Pathway for 2′,3′-Dideoxy, 2′3′-Didehydro Nucleoside Analogues

      Scheme 29

      Scheme 29. Acid-Catalyzed Decomposition Pathway for (O,S)-Acetals and Kinetic Data for Hydrolytic Degradation

      Scheme 30

      Scheme 30. Decomposition of 504 and Reassembly to Give 507 and Diol 508

      Scheme 31

      Scheme 31. Mechanism of the Acid-Catalyzed Hydrolysis of Thioketals

      Scheme 32

      Scheme 32. Metabolism of 526 in RLM

      Scheme 33

      Scheme 33. Mechanism of the Acid-Catalyzed Hydrolysis of (N,S)- (A) and (N,O)-Ketals (B)

      Scheme 34

      Scheme 34. Hydrolysis of 536537 and Structure of the Stable Analogue 538

      Scheme 35

      Scheme 35. Metabolism of 540

      Scheme 36

      Scheme 36. Mechanism of β-Lactamase Inhibition by 554

      Scheme 37

      Scheme 37. (A) Mechanism of β-Lactamase Inhibition by 557; (B) Reaction of 561 with Methoxide

      Scheme 38

      Scheme 38. Mechanism of the Acid-Catalyzed Hydrolysis of (N,N)-Aminals

      Scheme 39

      Scheme 39. Decomposition of 583 into 585

      Scheme 40

      Scheme 40. Structure of 586 and Degradation Pathways under Basic and Acidic Conditions

      Figure 23

      Figure 23. (A) The Bürgi–Dunitz angle for the approach of a nucleophile to the carbon atom of a carbonyl moiety; (B) details surrounding the interaction of the thiol of Cys225 with 610; (C) details associated with the interaction of the thiol of Cys225 with 612.

    • References

      ARTICLE SECTIONS
      Jump To

      This article references 288 other publications.

      1. 1
        McLay, I. M.; Halley, F.; Souness, J. E.; McKenna, J.; Benning, V.; Birrell, M.; Burton, B.; Belvisi, M.; Collis, A.; Constan, A.; Foster, M.; Hele, D.; Jayyosi, Z.; Kelley, M.; Maslen, C.; Miller, G.; Ouldelhkim, M. C.; Page, K.; Phipps, S.; Pollock, K.; Porter, B.; Ratcliffe, A. J.; Redford, E. J.; Webber, S.; Slater, B.; Thybaud, V.; Wilsher, N. The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy. Bioorg. Med. Chem. 2001, 9, 537554,  DOI: 10.1016/S0968-0896(00)00331-X
      2. 2
        Ndubaku, C. O.; Crawford, J. J.; Drobnick, J.; Aliagas, I.; Campbell, D.; Dong, P.; Dornan, L. M.; Duron, S.; Epler, J.; Gazzard, J.; Heise, C. E.; Hoeflich, K. P.; Jakubiak, D.; La, H.; Lee, W.; Lin, B.; Lyssikatos, J. P.; Maksimoska, J.; Marmorstein, R.; Murray, L. J.; O’Brien, T.; Oh, A.; Ramaswamy, S.; Wang, W.; Zhao, X.; Zhong, Y.; Blackwood, E.; Rudolph, J. Design of selective PAK1 inhibitor G-5555: improving properties by employing an unorthodox low pKa polar moiety. ACS Med. Chem. Lett. 2015, 6, 12411246,  DOI: 10.1021/acsmedchemlett.5b00398
      3. 3
        Khulbe, P.; Shrivastava, B.; Sharma, P.; Tiwari, A. K. In-situ buffered formulation: an effective approach for acid labile drug. Int. J. Pharm. Sci. Res. 2017, 8, 3544,  DOI: 10.13040/IJPSR.0975-8232.8(1).35-44
      4. 4
        Minchin, S.; Lodge, J. Understanding biochemistry: structure and function of nucleic acids. Essays Biochem. 2019, 63, 433456,  DOI: 10.1042/EBC20180038
      5. 5
        Stallforth, P.; Lepenies, B.; Adibekian, A.; Seeberger, P. H. Carbohydrates: a frontier in medicinal chemistry. J. Med. Chem. 2009, 52, 55615577,  DOI: 10.1021/jm900819p .
        (b) Ernst, B.; Magnani, J. L. From carbohydrate leads to glycomimetic drugs. Nat. Rev. Drug Discovery 2009, 8, 661677,  DOI: 10.1038/nrd2852 .
        (c) Galan, M. C.; Benito-Alifonso, D.; Watt, G. M. Carbohydrate chemistry in drug discovery. Org. Biomol. Chem. 2011, 9, 35983610,  DOI: 10.1039/c0ob01017k
      6. 6
        Wolfenden, R. Benchmark reaction rates, the stability of biological molecules in water, and the evolution of catalytic power in enzymes. Annu. Rev. Biochem. 2011, 80, 645667,  DOI: 10.1146/annurev-biochem-060409-093051
      7. 7
        (a) Beard, W. A.; Horton, J. K.; Prasad, R.; Wilson, S. H. Eukaryotic base excision repair: new approaches shine light on mechanism. Annu. Rev. Biochem. 2019, 88, 137162,  DOI: 10.1146/annurev-biochem-013118-111315 .
        (b) Drohat, A. C.; Maiti, A. Mechanisms for enzymatic cleavage of the N-glycosidic bond in DNA. Org. Biomol. Chem. 2014, 12, 83678378,  DOI: 10.1039/C4OB01063A
      8. 8
        Vocadlo, D. J.; Davies, S. G. Mechanistic insights into glycosidase chemistry. Curr. Opin. Chem. Biol. 2008, 12, 539555,  DOI: 10.1016/j.cbpa.2008.05.010
      9. 9
        (a) Yu, S.; Oh, J.; Li, F.; Kwon, Y.; Cho, H.; Shin, J.; Lee, S. K.; Kim, S. New scaffold for angiogenesis inhibitors discovered by targeted chemical transformations of wondonin natural products. ACS Med. Chem. Lett. 2017, 8, 10661071,  DOI: 10.1021/acsmedchemlett.7b00281 .
        (b) Huang, Z.; Williams, R. B.; Martin, S. M.; Lawrence, J. A.; Norman, V. L.; O’Neil-Johnson, M.; Harding, J.; Mangette, J. E.; Liu, S.; Guzzo, P. R.; Starks, C. M.; Eldridge, G. R. Bifidenone: structure-activity relationship and advanced preclinical candidate. J. Med. Chem. 2018, 61, 67366747,  DOI: 10.1021/acs.jmedchem.7b01644 .
        (c) Corey, E. J.; Wu, Y-. J. Total synthesis of (±)-paeoniflorigenin and paeoniflorin. J. Am. Chem. Soc. 1993, 115, 88718872,  DOI: 10.1021/ja00072a063 .
        (d) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. Total synthesis of halichondrin B and norhalichondrin B. J. Am. Chem. Soc. 1992, 114, 31623164,  DOI: 10.1021/ja00034a086 .
        (e) Fattorusso, C.; Persico, M.; Calcinai, B.; Cerrano, C.; Parapini, S.; Taramelli, D.; Novellino, E.; Romano, A.; Scala, F.; Fattorusso, E.; Taglialatela-Scafati, O. Manadoperoxides A-D from the Indonesian sponge Plakortis cfr. simplex. Further insights on the structure-activity relationships of simple 1,2-dioxane antimalarials. J. Nat. Prod. 2010, 73, 11381145,  DOI: 10.1021/np100196b .
        (f) Chevallier, O. P.; Graham, S. F.; Alonso, E.; Duffy, C.; Silke, J.; Campbell, K.; Botana, L. M.; Elliott, C. T. New insights into the causes of human illness due to consumption of azaspiracid contaminated shellfish. Sci. Rep. 2015, 5, 9818,  DOI: 10.1038/srep09818 .
        (g) Allan, K.; Stoltz, B. M. A concise total synthesis of (−)-quinocarcin via aryne annulation. J. Am. Chem. Soc. 2008, 130, 1727017271,  DOI: 10.1021/ja808112y .
        (h) Feng, X.; Bello, D.; Lowe, P. T.; Clark, J.; O’Hagan, D. Two 30-O-β-glucosylated nucleoside fluorometabolites related to nucleocidin in Streptomyces calvus. Chem. Sci. 2019, 10, 95019505,  DOI: 10.1039/C9SC03374B .
        (i) Whitley, R.; Alford, C.; Hess, F.; Buchanan, R. Vidarabine: a preliminary review of its pharmacological properties and therapeutic use. Drugs 1980, 20, 267282,  DOI: 10.2165/00003495-198020040-00002 .
        (j) Mazumder, A.; Dwivedi, A.; du Plessis, J. Sinigrin and its therapeutic benefits. Molecules 2016, 21, 416,  DOI: 10.3390/molecules21040416 .
        (k) Kim, C. S.; Oh, J.; Subedi, L.; Kim, S. Y.; Choi, S. U.; Lee, K. R. Rare thioglycosides from the roots of Wasabia japonica. J. Nat. Prod. 2018, 81, 21292133,  DOI: 10.1021/acs.jnatprod.8b00570 .
        (l) Igarashi, Y.; Asano, D.; Sawamura, M.; In, Y.; Ishida, T.; Imoto, M. Ulbactins F and G, polycyclic thiazoline derivatives with tumor cell migration inhibitory activity from Brevibacillus sp. Org. Lett. 2016, 18, 16581661,  DOI: 10.1021/acs.orglett.6b00531 .
        (m) Iwasa, E.; Hamashima, Y.; Fujishiro, S.; Higuchi, E.; Ito, A.; Yoshida, M.; Sodeoka, M. Total synthesis of (+)-chaetocin and its analogues: their histone methyltransferase G9a inhibitory activity. J. Am. Chem. Soc. 2010, 132, 40784079,  DOI: 10.1021/ja101280p .
        (n) Zipperer, A.; Konnerth, M.; Laux, C.; Berscheid, A.; Janek, D.; Weidenmaier, C.; Burian, M.; Schilling, N. A.; Slavetinsky, C.; Marschal, M.; Willmann, M.; Kalbacher, H.; Schittek, B.; Brötz-Oesterhelt, H.; Grond, S.; Peschel, A.; Krismer, B. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 2016, 535, 511516,  DOI: 10.1038/nature18634 .
        (o) Foo, K.; Newhouse, T.; Mori, I.; Takayama, H.; Baran, P. S. Total synthesis guided structure elucidation of (+)-psychotetramine. Angew. Chem., Int. Ed. 2011, 50, 27162719,  DOI: 10.1002/anie.201008048 .
        (p) Ohyabu, N.; Nishikawa, T.; Isobe, M. First asymmetric total synthesis of tetrodotoxin. J. Am. Chem. Soc. 2003, 125, 87988805,  DOI: 10.1021/ja0342998
      10. 10
        (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015, 58, 83158359,  DOI: 10.1021/acs.jmedchem.5b00258 .
        (b) Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 2018, 61, 58225880,  DOI: 10.1021/acs.jmedchem.7b01788 .
        (c) Liu, B.; Thayumanavan, S. Substituent effects on the pH sensitivity of acetals and ketals and their correlation with encapsulation stability in polymeric nanogels. J. Am. Chem. Soc. 2017, 139, 23062317,  DOI: 10.1021/jacs.6b11181
      11. 11
        (a) Gillies, E. R.; Goodwin, A. P.; Fréchet, J. M. Acetals as pH-sensitive linkages for drug delivery. Bioconjugate Chem. 2004, 15, 12541263,  DOI: 10.1021/bc049853x .
        (b) Gillies, E. R.; Fréchet, J. M. pH-Responsive copolymer assemblies for controlled release of doxorubicin. Bioconjugate Chem. 2005, 16, 361368,  DOI: 10.1021/bc049851c .
        (c) Huang, F.; Cheng, R.; Meng, F.; Deng, C.; Zhong, Z. Micelles based on acid degradable poly(acetal urethane): preparation, pH-sensitivity, and triggered intracellular drug release. Biomacromolecules 2015, 16, 22282236,  DOI: 10.1021/acs.biomac.5b00625 .
        (d) Cui, L.; Cohen, J. L.; Chu, C. K.; Wich, P. R.; Kierstead, P. H.; Fréchet, J. M. Conjugation chemistry through acetals toward a dextran-based delivery system for controlled release of siRNA. J. Am. Chem. Soc. 2012, 134, 1584015848,  DOI: 10.1021/ja305552u .
        (e) Hong, B. J.; Chipre, A. J.; Nguyen, S. T. Acid-degradable polymer-caged lipoplex (PCL) platform for siRNAdelivery: facile cellular triggered release of siRNA. J. Am. Chem. Soc. 2013, 135, 1765517658,  DOI: 10.1021/ja404491r .
        (f) Broaders, K. E.; Cohen, J. A.; Beaudette, T. T.; Bachelder, E. M.; Fréchet, J. M. Acetalated dextran is a chemically and biologically tunable material for particulate immunotherapy. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 54975502,  DOI: 10.1073/pnas.0901592106 .
        (g) Lee, S.; Wang, W.; Lee, Y.; Sampson, N. S. Cyclic acetals as cleavable linkers for affinity capture. Org. Biomol. Chem. 2015, 13, 84458452,  DOI: 10.1039/C5OB01056J
      12. 12
        Maryanoff, B. E. Phenotypic assessment and the discovery of topiramate. ACS Med. Chem. Lett. 2016, 7, 662665,  DOI: 10.1021/acsmedchemlett.6b00176
      13. 13
        Hale, J. L.; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. M.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. Structural optimization affording2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J. Med. Chem. 1998, 41, 46074614,  DOI: 10.1021/jm980299k
      14. 14
        Delost, M. D.; Smith, D. T.; Anderson, B. J.; Njardarson, J. T. From oxiranes to oligomers: architectures of U.S. FDA approved pharmaceuticals containing oxygen heterocycles. J. Med. Chem. 2018, 61, 1099611020,  DOI: 10.1021/acs.jmedchem.8b00876
      15. 15
        (a) De Wolfe, R. H.; Ivanetich, K. M.; Perry, N. F. General acid catalysis in benzophenone ketal hydrolysis. J. Org. Chem. 1969, 34, 848854,  DOI: 10.1021/jo01256a015 .
        (b) Fife, T. H. General acid catalysis of acetal, ketal, and ortho ester hydrolysis. Acc. Chem. Res. 1972, 5, 264272,  DOI: 10.1021/ar50056a002 .
        (c) Cordes, E. H.; Bull, H. G. Mechanism and catalysis for hydrolysis of acetals, ketals, and ortho esters. Chem. Rev. 1974, 74, 581603,  DOI: 10.1021/cr60291a004 .
        (d) Wasserman, H. H.; Clark, G. M.; Turley, P. C. Recent aspects of cyclopropanone chemistry. In: Stereochemistry I. Topics in Current Chemistry Fortschritte der Chemischen Forschung 1974, 47, 73156,  DOI: 10.1007/3-540-06648-9_9 .
        (e) Deslongchamps, P.; Dory, Y. L.; Li, S. The relative rate of hydrolysis of a series of acyclic and six-membered cyclic acetals, ketals, orthoesters, and orthocarbonates. Tetrahedron 2000, 56, 35333537,  DOI: 10.1016/S0040-4020(00)00270-2 .
        (f) Li, S.; Dory, Y. L.; Deslongchamps, P. On the relative rate of hydrolysis of a series of ketals and their proton affinities. Isr. J. Chem. 2000, 40, 209215,  DOI: 10.1560/QRH5-Q3N0-0XA6-PT9Y .
        (g) Repetto, S. L.; Costello, J. F.; Butts, C. P.; Lam, J. K. W.; Ratcliffe, N. M. The hydrolysis of geminal ethers: a kinetic appraisal of orthoesters and ketals. Beilstein J. Org. Chem. 2016, 12, 14671475,  DOI: 10.3762/bjoc.12.143 .
        (h) Salomaa, P.; Kankaanpera, A.; Norin, T. The hydrolysis of 1,3-dioxolan and its alkyl-substituted derivatives. Part I. the structural factors influencing the rates of hydrolysis of a series of methyl-substituted dioxolans. Acta Chem. Scand. 1961, 15, 871878,  DOI: 10.3891/acta.chem.scand.15-0871 .
        (i) Jacques, S. A.; Leriche, G.; Mosser, M.; Nothisen, M.; Muller, C. D.; Remy, J.-S.; Wagner, A. From solution to in-cell study of the chemical reactivity of acid sensitive functional groups: a rational approach towards improved cleavable linkers for biospecific endosomal release. Org. Biomol. Chem. 2016, 14, 47944803,  DOI: 10.1039/C6OB00846A
      16. 16
        Blanco-Ania, D.; Rutjes, F. P. J. T. Carbonylonium ions: the onium ions of the carbonyl group. Beilstein J. Org. Chem. 2018, 14, 25682571,  DOI: 10.3762/bjoc.14.233
      17. 17
        (a) Fife, T. H.; Hagopian, L. Steric effects in ketal hydrolysis. J. Org. Chem. 1966, 31, 17721775,  DOI: 10.1021/jo01344a024 .
        (b) McClelland, R. A.; Watada, B.; Lew, C. S. Q. Reversibility of the ring-opening step in the acid hydrolysis of cyclic acetophenone acetals. J. Chem. Soc., Perkin Trans. 2 1993, 17231727,  DOI: 10.1039/p29930001723 .
        (c) Knowles, J. P.; Whiting, A. The effects of ring size and substituents on the rates of acid-catalysed hydrolysis of five- and six-membered ring cyclic ketone acetals. Eur. Eur. J. Org. Chem. 2007, 2007, 33653368,  DOI: 10.1002/ejoc.200700244 .
        (d) Liu, B.; Thayumanavan, S. Substituent effects on the pH sensitivity of acetals and ketals and their correlation with encapsulation stability in polymeric nanogels. J. Am. Chem. Soc. 2017, 139, 23062317,  DOI: 10.1021/jacs.6b11181
      18. 18
        Miller, S. R.; Krasutsky, S.; Kiprof, P. Stability of carboxonium ions. J. Mol. Struct.: THEOCHEM 2004, 674, 4347,  DOI: 10.1016/j.theochem.2003.12.044
      19. 19
        Carey, F. A.; Sundberg, R. J. Reaction of Carbonyl Compounds. Advanced Organic Chemistry 1977, 325360,  DOI: 10.1007/978-1-4613-9792-2_8
      20. 20
        (a) Guthrie, J. P. Carbonyl addition reactions. Factors affecting the hydrate-hemiacetal and hemiacetal-acetal equilibrium constants. Can. J. Chem. 1975, 53, 898906,  DOI: 10.1139/v75-125 .
        (b) Greenzaid, P.; Luz, Z.; Samuel, D. A nuclear magnetic resonance study of the reversible hydration of aliphatic aldehydes and ketones. I. Oxygen-17 and proton spectra and equilibrium constants. J. Am. Chem. Soc. 1967, 89, 749756,  DOI: 10.1021/ja00980a004
      21. 21
        Butler, T. C. The introduction of chloral hydrate into medical practice. Bull. Hist. Med. 1970, 44, 168172
      22. 22
        (a) West, R. Siegfried Ruhemann and the discovery of ninhydrin. J. Chem. Educ. 1965, 42, 386388,  DOI: 10.1021/ed042p386 .
        (b) Odén, S.; von Hofsten, B. Detection of fingerprints by the ninhydrin reaction. Nature 1954, 173, 449450,  DOI: 10.1038/173449a0
      23. 23
        Simmons, H. E.; Wiley, D. W. Fluoroketones. J. Am. Chem. Soc. 1960, 82, 22882296,  DOI: 10.1021/ja01494a047
      24. 24
        Bagnall, R. D.; Bell, W.; Pearson, K. New inhalation anaesthetics: I. Fluorinated 1,3-dioxolane derivatives. J. Fluorine Chem. 1977, 9, 359375,  DOI: 10.1016/S0022-1139(00)82169-7
      25. 25
        Brown, H. C.; Okamoto, Y. Substituent constants for aromatic substitution. J. Am. Chem. Soc. 1957, 79, 19131917,  DOI: 10.1021/ja01565a039
      26. 26
        Lowe, D. In The Pipeline. https://blogs.sciencemag.org/pipeline/archives/2015/11/05/another-funny-looking-structure-comes-through (accessed March 12, 2021).
      27. 27
        ClinCalc DrugStats Database. https://clincalc.com/DrugsStats/Top300Drugs.aspx (accessed April 6, 2021).
      28. 28
        Maryanoff, B. E.; Costanzo, M. J.; Nortey, S. O.; Greco, M. N.; Shank, R. P.; Schupsky, J. J.; Ortegon, M. P.; Vaught, J. L. Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives. J. Med. Chem. 1998, 41, 13151343,  DOI: 10.1021/jm970790w
      29. 29
        Rankovic, Z. CNS drug design: balancing physicochemical properties for optimal brain exposure. J. Med. Chem. 2015, 58, 25842608,  DOI: 10.1021/jm501535r
      30. 30
        Brand, S.; Norcross, N. R.; Thompson, S.; Harrison, J. R.; Smith, V. C.; Robinson, D. A.; Torrie, L. S.; McElroy, S. P.; Hallyburton, I.; Norval, S.; Scullion, P.; Stojanovski, L.; Simeons, F. R.; Aalten, D. V.; Frearson, J. A.; Brenk, R.; Fairlamb, A. H.; Ferguson, M. A.; Wyatt, P. G.; Gilbert, I. H.; Read, K. D. Lead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-!myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis. J. Med. Chem. 2014, 57, 98559869,  DOI: 10.1021/jm500809c
      31. 31
        Christensen, J.; Højskov, C. S.; Dam, M.; Poulsen, J. H. Plasma concentration of topiramate correlates with cerebrospinal fluid concentration. Ther. Drug Monit. 2001, 23, 529535,  DOI: 10.1097/00007691-200110000-00006
      32. 32
        Caldwell, G. W.; Wu, W. N.; Masucci, J. A.; McKown, L. A.; Gauthier, D.; Jones, W. J.; Leo, G. C.; Maryanoff, B. E. Metabolism and excretion of the antiepileptic/antimigraine drug, topiramate in animals and humans. Eur. J. Drug Metab. Pharmacokinet. 2005, 30, 151164,  DOI: 10.1007/BF03190614
      33. 33
        Patsalos, P. N. The mechanism of action of topiramate. Rev. Contemp. Pharmacother. 1999, 10, 147153
      34. 34
        (a) Monteiro, J.; Alves, M. G.; Oliveira, P. F.; Silva, B. M. Pharmacological potential of methylxanthines: Retrospective analysis and future expectations. Crit. Rev. Food Sci. Nutr. 2019, 59, 25972625,  DOI: 10.1080/10408398.2018.1461607 .
        (b) Matera, M. G.; Page, C. P.; Calzetta, L.; Rogliani, P.; Cazzola, M. Pharmacology and therapeutics of bronchodilators revisited. Pharmacol. Rev. 2020, 72, 218252,  DOI: 10.1124/pr.119.018150
      35. 35
        (a) Shukla, D.; Chakraborty, S.; Singh, S.; Mishra, B. Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. Expert Opin. Pharmacother. 2009, 10, 23432356,  DOI: 10.1517/14656560903200667 .
        (b) Matera, M. G.; Page, C.; Cazzola, M. Doxofylline is not just another theophylline!. Int. J. Chronic Obstruct. Pulm. Dis. 2017, 12, 34873493,  DOI: 10.2147/COPD.S150887
      36. 36
        (a) Zhao, X.; Ma, H.; Pan, Q.; Wang, H.; Qian, X.; Song, P.; Zou, L.; Mao, M.; Xia, S.; Ge, G.; Yang, L. Theophylline acetaldehyde as the initial product in doxophylline metabolism in human liver. Drug Metab. Dispos. 2020, 48, 345352,  DOI: 10.1124/dmd.119.089565 .
        (b) Grosa, G.; Franzone, J. S.; Biglino, G. Metabolism of doxophylline by rat liver microsomes. Drug Metab. Dispos. 1986, 14, 267270
      37. 37
        Griebel, G.; Stemmelin, J.; Lopez-Grancha, M.; Fauchey, V.; Slowinski, F.; Pichat, P.; Dargazanli, G.; Abouabdellah, A.; Cohen, C.; Bergis, O. E. The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents. Sci. Rep. 2018, 8, 2416,  DOI: 10.1038/s41598-018-20895-z
      38. 38
        Garde, D. J&J halts a depression program in the shadow of a fatal French trial. https://www.fiercebiotech.com/r-d/j-j-halts-a-depression-program-shadow-of-a-fatal-french-trial (accessed March 17, 2021).
      39. 39
        Belema, M.; Meanwell, N. A. Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect. J. Med. Chem. 2014, 57, 50575071,  DOI: 10.1021/jm500335h
      40. 40
        (a) Kazmierski, W. W.; Maynard, A.; Duan, M.; Baskaran, S.; Botyanszki, J.; Crosby, R.; Dickerson, S.; Tallant, M.; Grimes, R.; Hamatake, R.; Leivers, M.; Roberts, C. D.; Walker, J. Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound. J. Med. Chem. 2014, 57, 20582073,  DOI: 10.1021/jm4013104 .
        (b) Wilfret, D. A.; Walker, J.; Adkison, K. K.; Jones, L. A.; Lou, Y.; Gan, J.; Castellino, S.; Moseley, C. L.; Horton, J.; de Serres, M.; Culp, A.; Goljer, I.; Spreen, W. Safety, tolerability, pharmacokinetics, and antiviral activity of GSK2336805, an inhibitor of hepatitis C virus (HCV) NS5A, in healthy subjects and subjects chronically infected with HCV genotype 1. Antimicrob. Agents Chemother. 2013, 57, 50375044,  DOI: 10.1128/AAC.00910-13
      41. 41
        Tai, V. W.; Garrido, D.; Price, D. J.; Maynard, A.; Pouliot, J. J.; Xiong, Z.; Seal III, J. W.; Creech, K. L.; Kryn, L. H.; Baughman, T. M.; Peat, A. J. Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein. Bioorg. Med. Chem. Lett. 2014, 24, 22882294,  DOI: 10.1016/j.bmcl.2014.03.080
      42. 42
        (a) Chen, K. X.; Njoroge, G.; Arasappan, A.; Venkatraman, S.; Vibulbhan, B.; Yang, W.; Parekh, T. N.; Pichardo, J.; Prongay, A.; Cheng, K.; Butkiewicz, N.; Yao, N.; Madison, V.; Girijavallabhan, V. Novel potent hepatitis C virus NS3 serine protease inhibitors derived from proline-based macrocycles. J. Med. Chem. 2006, 49, 9951005,  DOI: 10.1021/jm050820s .
        (b) Chen, K. X.; Njoroge, F. G.; Vibulbhan, B.; Prongay, A.; Pichardo, J.; Madison, V.; Buevich, A.; Chan, T. M. Proline-based macrocyclic inhibitors of the hepatitis C virus: stereoselective synthesis and biological activity. Angew. Chem., Int. Ed. 2005, 44, 70247028,  DOI: 10.1002/anie.200501553
      43. 43
        (a) Sanglier, J.-J.; Quesniaux, V.; Fehr, T.; Hofmann, H.; Mahnke, M.; Memmert, K.; Schuler, W.; Zenke, G.; Gschwind, L.; Maurer, C.; Schilling, W. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92–308110: I. Taxonomy, fermentation, isolation and biological activity. J. Antibiot. 1999, 52, 466473,  DOI: 10.7164/antibiotics.52.466 .
        (b) Fehr, T.; Kallen, J.; Oberer, L.; Sanglier, J.-J.; Schilling, W. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92–308110: II. Structure elucidation, stereochemistry and physico-chemical properties. J. Antibiot. 1999, 52, 474479,  DOI: 10.7164/antibiotics.52.474
      44. 44
        Mackman, R.; Steadman, V. A.; Dean, D. K.; Jansa, P.; Poullennec, K. G.; Appleby, T.; Austin, C.; Blakemore, C. A.; Cai, R.; Cannizzaro, C.; Chin, G.; Chiva, J. C.; Dunbar, N. A.; Fliri, H.; Highton, A. J.; Hui, H.; Ji, M.; Jin, H.; Karki, K.; Keats, A. J.; Lazarides, L.; Lee, Y.; Liclican, A.; Mish, M.; Murray, B.; Pettit, S. B.; Yun, P.; Sangi, M.; Santos, R.; Sanvoisin, J.; Schmitz, U.; Schrier, A.; Siegel, D.; Sperandio, D.; Stepan, G.; Tian, Y.; Watt, G. M.; Yang, H.; Schultz, B. E. Discovery of a potent and orally bioavailable cyclophilin inhibitor derived from the sanglifehrin macrocycle. J. Med. Chem. 2018, 61, 94739499,  DOI: 10.1021/acs.jmedchem.8b00802
      45. 45
        Ma, X.; Idle, J. R.; Gonzalez, F. J. The pregnane X receptor: from bench to bedside. Expert Opin. Drug Metab. Toxicol. 2008, 4, 895908,  DOI: 10.1517/17425255.4.7.895
      46. 46
        Wang, Y.; Zhao, H.; Brewer, J. T.; Li, H.; Lao, Y.; Amberg, W.; Behl, B.; Akritopoulou-Zanze, I.; Dietrich, J.; Lange, U. E.; Pohlki, F.; Hoft, C.; Hornberger, W.; Djuric, S. W.; Sydor, J.; Mezler, M.; Relo, A. L.; Vasudevan, A. De novo design, synthesis, and biological evaluation of 3,4-disubstituted pyrrolidine sulfonamides as potent and selective glycine transporter 1 competitive inhibitors. J. Med. Chem. 2018, 61, 74867502,  DOI: 10.1021/acs.jmedchem.8b00295
      47. 47
        (a) Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 2009, 52, 67526756,  DOI: 10.1021/jm901241e .
        (b) Hirata, K.; Kotoku, M.; Seki, N.; Maeba, T.; Maeda, K.; Hirashima, S.; Sakai, T.; Obika, S.; Hori, A.; Hase, Y.; Yamaguchi, T.; Katsuda, Y.; Hata, T.; Miyagawa, N.; Arita, K.; Nomura, Y.; Asahina, K.; Aratsu, Y.; Kamada, M.; Adachi, T.; Noguchi, M.; Doi, S.; Crowe, P.; Bradley, E.; Steensma, R.; Tao, H.; Fenn, M.; Babine, R.; Li, X.; Thacher, S.; Hashimoto, H.; Shiozaki, M. SAR Exploration guided by LE and Fsp3: discovery of a selective and orally efficacious RORδ inhibitor. ACS Med. Chem. Lett. 2016, 7, 2327,  DOI: 10.1021/acsmedchemlett.5b00253
      48. 48
        Stojanovic-Radic, Z.; Pejic, M.; Dimitrijevic, M.; Aleksic, A.; Kumar, N. V.; Salehi, B.; Cho, W. C.; Sharifi-Rad, J. Piperine - a major principle of black pepper: a review of its bioactivity and studies. Appl. Sci. 2019, 9, 4270,  DOI: 10.3390/app9204270
      49. 49
        (a) Bertelsen, K. M.; Venkatakrishnan, K.; von Moltke, L. L.; Obach, R. S.; Greenblatt, D. J. Apparent mechanism-based inhibition of human CYP 2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab. Dispos. 2003, 31, 289293,  DOI: 10.1124/dmd.31.3.289 .
        (b) Kamel, E. M.; Lamsabhi, A. M. The quasi-irreversible inactivation of Cytochrome P450 enzymes by paroxetine: A computational approach. Org. Biomol. Chem. 2020, 18, 33343345,  DOI: 10.1039/D0OB00529K .
        (c) Zhao, S. X.; Dalvie, D. K.; Kelly, J. M.; Soglia, J. R.; Frederick, K. S.; Smith, E. B.; Obach, R. S.; Kalgutkar, A. S. NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. Chem. Res. Toxicol. 2007, 20, 16491657,  DOI: 10.1021/tx700132x
      50. 50
        (a) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A.-C.; Coste, H.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. The discovery of tadalafil: a novel and highly selective PDE5 Inhibitor. 1:5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues. J. Med. Chem. 2003, 46, 45254532,  DOI: 10.1021/jm030056e .
        (b) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A. C.; Coste, H.; Linget, J. M.; Kirilovsky, J.; Hyafil, F.; Labaudinière, R. The discovery of tadalafil: a novel and highly selective PDE5 Inhibitor. 2:2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione analogues. J. Med. Chem. 2003, 46, 45334542,  DOI: 10.1021/jm0300577 .
        (c) Curran, M. P.; Keating, G. M. Tadalafil. Drugs 2003, 63, 22032212,  DOI: 10.2165/00003495-200363200-00004
      51. 51
        Hartmann, J. T.; Lipp, H.-P. Camptothecin and podophyllotoxin derivatives inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profile. Drug Saf. 2006, 29, 209230,  DOI: 10.2165/00002018-200629030-00005
      52. 52
        Murray, M. Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Curr. Drug Metab. 2000, 1, 6784,  DOI: 10.2174/1389200003339270
      53. 53
        Bardin, E.; Pastor, A.; Semeraro, M.; Golec, A.; Hayes, K.; Chevalier, B.; Berhal, F.; Prestat, G.; Hinzpeter, A.; Gravier-Pelletier, C.; Pranke, I.; Sermet-Gaudelus, I. Modulators of CFTR. Updates on clinical development and future directions. Eur. J. Med. Chem. 2021, 213, 113195,  DOI: 10.1016/j.ejmech.2021.113195
      54. 54
        Keith, J. M.; Jones, W. M.; Tichenor, M.; Liu, J.; Seierstad, M.; Palmer, J. A.; Webb, M.; Karbarz, M.; Scott, B. P.; Wilson, S. J.; Luo, L.; Wennerholm, M. L.; Chang, L.; Rizzolio, M.; Rynberg, R.; Chaplan, S. R.; Breitenbucher, J. G. Preclinical characterization of the FAAH inhibitor JNJ-42165279. ACS Med. Chem. Lett. 2015, 6, 12041208,  DOI: 10.1021/acsmedchemlett.5b00353
      55. 55
        Rose, W. C.; Marathe, P. H.; Jang, G. R.; Monticello, T. M.; Balasubramanian, B. N.; Long, B.; Fairchild, C. R.; Wall, M. E.; Wani, M. C. Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization. Cancer Chemother. Pharmacol. 2006, 58, 7385,  DOI: 10.1007/s00280-005-0128-y
      56. 56
        Alig, L.; Alsenz, J.; Andjelkovic, M.; Bendels, S.; Bénardeau, A.; Bleicher, K.; Bourson, A.; David-Pierson, P.; Guba, W.; Hildbrand, S.; Kube, D.; Lübbers, T.; Mayweg, A. V.; Narquizian, R.; Neidhart, W.; Nettekoven, M.; Plancher, J.; Rocha, C.; Rogers-Evans, M.; Röver, S.; Schneider, G.; Taylor, S.; Waldmeier, P. Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity. J. Med. Chem. 2008, 51, 21152127,  DOI: 10.1021/jm701487t
      57. 57
        (a) Boyle, C. D.; Chackalamannil, S.; Chen, L.; Dugar, S.; Pushpavanam, P.; Billard, W.; Binch, H.; Crosby, H.; Cohen-Williams, M.; Coffin, V. L.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E. Benzylidene ketal derivatives as M2 muscarinic receptor antagonists. Bioorg. Med. Chem. Lett. 2000, 10, 27272730,  DOI: 10.1016/S0960-894X(00)00553-9 .
        (b) Boyle, C. D.; Chackalamannil, S.; Clader, J. W.; Greenlee, W. J.; Josien, H. B.; Kaminski, J. J.; Kozlowski, J. A.; McCombie, S. W.; Nazareno, D. V.; Tagat, J. R.; Wang, Y.; Zhou, G.; Billard, W.; Binch, H.; Crosby, G.; Cohen-Williams, M.; Coffin, V. L.; Cox, K. A.; Grotz, D. E.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E. Metabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitution. Bioorg. Med. Chem. Lett. 2001, 11, 23112314,  DOI: 10.1016/S0960-894X(01)00435-8
      58. 58
        (a) Franchini, S.; Sorbi, C.; Linciano, P.; Carnevale, G.; Tait, A.; Ronsisvalle, S.; Buccioni, M.; Del Bello, F.; Cilia, A.; Pirona, L.; Denora, N.; Iacobazzi, R. M.; Brasili, L. 1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity. Eur. J. Med. Chem. 2019, 176, 310325,  DOI: 10.1016/j.ejmech.2019.05.024 .
        (b) Linciano, P.; Sorbi, C.; Comitato, A.; Lesniak, A.; Bujalska-Zadrożny, M.; Pawłowska, A.; Bielenica, A.; Orzelska-Górka, J.; Kedzierska, E.; Biała, G.; Ronsisvalle, S.; Limoncella, S.; Casarini, L.; Cichero, E.; Fossa, P.; Satała, G.; Bojarski, A. J.; Brasili, L.; Bardoni, R.; Franchini, S. Identification of a potent and selective 5-HT1A receptor agonist with in vitro and in vivo antinociceptive activity. ACS Chem. Neurosci. 2020, 11, 41114127,  DOI: 10.1021/acschemneuro.0c00289
      59. 59
        (a) Dunn, M. I. A new antihypertensive drug. JAMA, J. Am. Med. Assoc. 1981, 245, 16391642,  DOI: 10.1001/jama.245.16.1639 .
        (b) Hengstmann, J. H.; Falkner, F. C. Disposition of guanethidine during chronic oral therapy. Eur. J. Clin. Pharmacol. 1979, 15, 121125,  DOI: 10.1007/BF00609875 .
        (c) Finnerty, F. A., Jr.; Brogden, R. N. Guanadrel, A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in hypertension. Drugs 1985, 30, 2231,  DOI: 10.2165/00003495-198530010-00003
      60. 60
        (a) Satoh, E.; Kasahara, R.; Fukatsu, K.; Aoki, T.; Harayama, H.; Murata, T. Benzpyrimoxan: design, synthesis, and biological activity of a novel insecticide. J. Pestic. Sci. 2021, 46, 109114,  DOI: 10.1584/jpestics.D20-069 .
        (b) Umetsu, N.; Shirai, Y. Development of novel pesticides in the 21st century. J. Pestic. Sci. 2020, 45, 5474,  DOI: 10.1584/jpestics.D20-201
      61. 61
        (a) McAtee, L. C.; Sutton, S. W.; Rudolph, D. A.; Li, X.; Aluisio, L. E.; Phuong, V. K.; Dvorak, C. A.; Lovenberg, T. W.; Carruthers, N. I.; Jones, T. K. Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX2R) antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 42254229,  DOI: 10.1016/j.bmcl.2004.06.032 .
        (b) Letavic, M. A.; Bonaventure, P.; Carruthers, N. I.; Dugovic, C.; Koudriakova, T.; Lord, B.; Lovenberg, T. W.; Ly, K. S.; Mani, N. S.; Nepomuceno, D.; Pippel, D. J.; Rizzolio, M.; Shelton, J. E.; Shah, C. R.; Shireman, B. T.; Young, L. K.; Yun, S. Novel octahydropyrrolo[3,4-c]pyrroles are selective orexin-2 antagonists: SAR leading to a clinical candidate. J. Med. Chem. 2015, 58, 56205636,  DOI: 10.1021/acs.jmedchem.5b00742
      62. 62
        (a) Trabocchi, A.; Menchi, G.; Guarna, F.; Machetti, F.; Scarpi, D.; Guarna, A. Design, synthesis, and applications of 3-aza-6,8-dioxabicyclo[3.2.1]octane-based scaffolds for peptidomimetic chemistry. Synlett 2006, 2006, 03310353,  DOI: 10.1055/s-2006-926249 .
        (b) Trabocchi, A.; Cini, N.; Menchi, G.; Guarna, A. A new bicyclic proline-mimetic amino acid. Tetrahedron Lett. 2003, 44, 34893492,  DOI: 10.1016/S0040-4039(03)00663-4 .
        (c) Trabocchi, A.; Menchi, G.; Danieli, E.; Guarna, A. Synthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostere. Amino Acids 2008, 35, 3744,  DOI: 10.1007/s00726-007-0636-7 .
        (d) Machetti, F.; Bucelli, I.; Indiani, G.; Guarna, A. Neat reaction of carboxylic acid methyl esters and amines for efficient parallel synthesis of scaffold amide libraries. C. R. Chim. 2003, 6, 631633,  DOI: 10.1016/S1631-0748(03)00097-3 .
        (e) Cini, N.; Danieli, E.; Menchi, G.; Trabocchi, A.; Bottoncetti, A.; Raspanti, S.; Pupi, A.; Guarna, A. 3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter. Bioorg. Med. Chem. 2006, 14, 51105120,  DOI: 10.1016/j.bmc.2006.04.019
      63. 63
        (a) Sherwood, J.; De bruyn, M.; Constantinou, A.; Moity, L.; McElroy, C. R.; Farmer, T. J.; Duncan, T.; Raverty, W.; Hunt, A. J.; Clark, J. H. Dihydrolevoglucosenone (Cyrene) as a bio-based alternative for dipolar aprotic solvents. Chem. Commun. 2014, 50, 96509652,  DOI: 10.1039/C4CC04133J .
        (b) Hughes, L.; McElroy, C. R.; Whitwood, A. C.; Hunt, A. J. Development of pharmaceutically relevant biobased intermediates though aldol condensation and Claisen-Schmidt reactions of dihydrolevoglucosenone (Cyrene®). Green Chem. 2018, 20, 44234427,  DOI: 10.1039/C8GC01227J .
        (c) Liu, X.; Carr, P.; Gardiner, M. G.; Banwell, M. G.; Elbanna, A. H.; Khalil, Z. G.; Capon, R. J. Levoglucosenone and its pseudoenantiomer iso-levoglucosenone as scaffolds for drug discovery and development. ACS Omega 2020, 5, 1392613939,  DOI: 10.1021/acsomega.0c01331
      64. 64
        (a) Sensi, P. History of the development of rifampin. Clin. Infect. Dis. 1983, 5, S402S406,  DOI: 10.1093/clinids/5.Supplement_3.S402 .
        (b) Wehrli, W.; Staehelin, M. Rifamycins and other ansamycins. Mechanism of Action of Antimicrobial and Antitumor Agents. Antibiotics. 1975, 3, 252268,  DOI: 10.1007/978-3-642-46304-4_16
      65. 65
        (a) Oppolzer, W.; Prelog, V.; Sensi, P. The composition of rifamycin B and related rifamycins. Experientia 1964, 20, 336339,  DOI: 10.1007/BF02171084 .
        (b) Leitich, J.; Oppolzer, W.; Prelog, V. On the configuration of rifamycin B and related rifamycins. Experientia 1964, 20, 343344,  DOI: 10.1007/BF02171086
      66. 66
        Bacchi, A.; Pelizzi, G.; Nebuloni, M.; Ferrari, P. Comprehensive study on structure-activity relationships of rifamycins: discussion of molecular and crystal structure and spectroscopic and thermochemical properties of rifamycin O. J. Med. Chem. 1998, 41, 23192332,  DOI: 10.1021/jm970791o
      67. 67
        Bergamini, N.; Fowst, G. Rifamycin SV. A review. Arzneim.-Forsch. 1965, 15 (Suppl), 9511002
      68. 68
        Rode, H. B.; Lade, D. M.; Grée, R.; Mainkar, P. S.; Chandrasekhar, S. Strategies towards the synthesis of anti-tuberculosis drugs. Org. Biomol. Chem. 2019, 17, 54285459,  DOI: 10.1039/C9OB00817A
      69. 69
        (a) Loos, U.; Musch, E.; Jensen, J. C.; Mikus, G.; Schwabe, H. K.; Eichelbaum, M. Pharmacokinetics of oral and intravenous rifampicin during chronic administration. Klin. Wochenschr. 1985, 63, 12051211,  DOI: 10.1007/BF01733779 .
        (b) Acocella, G. Clinical pharmacokinetics of rifampicin. Clin. Pharmacokinet. 1978, 3, 108127,  DOI: 10.2165/00003088-197803020-00002
      70. 70
        Campbell, E. A.; Korzheva, N.; Mustaev, A.; Murakami, K.; Nair, S.; Goldfarb, A.; Darst, S. A. Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell 2001, 104, 901912,  DOI: 10.1016/S0092-8674(01)00286-0
      71. 71
        Brogden, R. N.; Fitton, A. Rifabutin. Drugs 1994, 47, 9831009,  DOI: 10.2165/00003495-199447060-00008
      72. 72
        (a) Skinner, M. H.; Blaschke, T. F. Clinical pharmacokinetics of rifabutin. Clin. Pharmacokinet. 1995, 28, 115125,  DOI: 10.2165/00003088-199528020-00003 .
        (b) Blaschke, T. F.; Skinner, M. H. The clinical pharmacokinetics of rifabutin. Clin. Infect. Dis. 1996, 22, S15S22,  DOI: 10.1093/clinids/22.Supplement_1.S15
      73. 73
        Stahelin, H. F.; von Wartburg, A. The chemical and biological route from podophyllotoxin glucoside to etoposide: ninth Cain Memorial Award Lecture. Cancer Res. 1991, 51, 515
      74. 74
        (a) Joel, S. P.; Clark, P. I.; Heap, L.; Webster, L.; Robbins, S.; Craft, H.; Slevin, M. L. Pharmacological attempts to improve the bioavailability of oral etoposide. Cancer Chemother. Pharmacol. 1995, 37, 125133,  DOI: 10.1007/BF00685639 .
        (b) Shah, J. C.; Chen, J. R.; Chow, D. Preformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposide. Pharm. Res. 1989, 6, 408412,  DOI: 10.1023/A:1015935532725 .
        (c) Toffoli, G.; Corona, G.; Basso, B.; Boiocchi, M. Pharmacokinetic optimization of treatment with oral etoposide. Clin. Pharmacokinet. 2004, 43, 441466,  DOI: 10.2165/00003088-200443070-00002
      75. 75
        (a) Saulnier, M. G.; Langley, D.; Kadow, J. F.; Senter, P. D.; Knipe, J.; Tun, M. M.; Vyas, D. M.; Doyle, T. W. Synthesis of etoposide phosphate, BMY-40481, a water-soluble clinically active prodrug of etoposide. Bioorg. Med. Chem. Lett. 1994, 4, 25672572,  DOI: 10.1016/S0960-894X(01)80285-7 .
        (b) Chabot, G G; Armand, J P; Terret, C; de Forni, M; Abigerges, D; Winograd, B; Igwemezie, L; Schacter, L; Kaul, S; Ropers, J; Bonnay, M Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I study. J. Clin. Oncol. 1996, 14, 20202030,  DOI: 10.1200/JCO.1996.14.7.2020
      76. 76
        (a) Heimbach, T.; Oh, D.-M.; Li, L. Y; Rodrıguez-Hornedo, N.ır; Garcia, G.; Fleisher, D. Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs. Int. J. Pharm. 2003, 261, 8192,  DOI: 10.1016/S0378-5173(03)00287-4 .
        (b) Heimbach, T.; Oh, D. M.; Li, L. Y.; Forsberg, M.; Savolainen, J.; Leppänen, J.; Matsunaga, Y.; Flynn, G.; Fleisher, D. Absorption rate limit considerations for oral phosphate prodrugs. Pharm. Res. 2003, 20, 848856,  DOI: 10.1023/A:1023827017224
      77. 77
        Long, B. H. Mechanisms of action of teniposide (VM-26) and comparison with etoposide (VP-16). Semin. Oncol. 1992, 19 (Suppl. 6), 319
      78. 78
        (a) Splinter, T. A.; Holthuis, J. J.; Kok, T. C.; Post, M. H. Absolute bioavailability and pharmacokinetics of oral teniposide. Semin. Oncol. 1992, 19 (Suppl. 6), 2834.
        (b) Relling, M. V.; Evans, R.; Dass, C.; Desiderio, D. M.; Nemec, J. Human cytochrome P450 metabolism of teniposide and etoposide. J. Pharmacol. Exp. Ther. 1992, 261, 491496
      79. 79
        Jacob, D. A.; Mercer, S. L.; Osheroff, N.; Deweese, J. E. Etoposide quinone is a redox-dependent topoisomerase II poison. Biochemistry 2011, 50, 56605667,  DOI: 10.1021/bi200438m
      80. 80
        Yang, J.; Bogni, A.; Schuetz, E. G.; Ratain, M.; Dolan, M. E.; McLeod, H.; Gong, L.; Thorn, C.; Relling, M. V.; Klein, T. E.; Altman, R. B. Etoposide pathway. Pharmacogenet. Genomics 2009, 19, 552553,  DOI: 10.1097/FPC.0b013e32832e0e7f
      81. 81
        Pui, C. H.; Ribeiro, R. C.; Hancock, M. L.; Rivera, G. K.; Evans, W.; Raimondi, S. C.; Head, D. R.; Behm, F. G.; Mahmoud, M. H.; Sandlund, J. T.; Crist, W. M. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N. Engl. J. Med. 1991, 325, 16821687,  DOI: 10.1056/NEJM199112123252402
      82. 82
        Ashton, M. J.; Lawrence, C.; Karlsson, J.; Stuttle, K. A.; Newton, C. G.; Vacher, B. Y.; Webber, S.; Withnall, M. J. Anti-inflammatory 17β-thioalkyl-16α,17α-ketal and -acetal androstanes: a new class of airway selective steroids for the treatment of asthma. J. Med. Chem. 1996, 39, 48884896,  DOI: 10.1021/jm9604639
      83. 83
        (a) Gupta, R.; Jindal, D. P.; Kumar, G. Corticosteroids: the mainstay in asthma therapy. Bioorg. Med. Chem. 2004, 12, 63316342,  DOI: 10.1016/j.bmc.2004.05.045 .
        (b) Ye, Q.; He, X.; D’Urzo, A. A review on the safety and efficacy of inhaled corticosteroids in the management of asthma. Pulmon. Ther. 2017, 3, 118,  DOI: 10.1007/s41030-017-0043-5
      84. 84
        Edsbäcker, S.; Andersson, P.; Lindberg, C.; Ryrfeldt, A.; Thalén, A. Metabolic acetal splitting of budesonide. A novel inactivation pathway for topical glucocorticoids. Drug Metab. Dispos. 1987, 15, 412417
      85. 85
        Spencer, C. M.; McTavish, D. A review of its pharmacological properties and therapeutic efficacy in inflammatory bowel disease. Drugs 1995, 50, 854872,  DOI: 10.2165/00003495-199550050-00006
      86. 86
        de Weger, V. A.; Beijnen, J. H.; Schellens, J. H. M. Cellular and clinical pharmacology of the taxanes docetaxel and paclitaxel - a review. Anti-Cancer Drugs 2014, 25, 488494,  DOI: 10.1097/CAD.0000000000000093
      87. 87
        (a) Yassine, F.; Salibi, E.; Gali-Muhtasib, H. Overview of the formulations and analogues in the taxanes&. story. Curr. Med. Chem. 2016, 23, 45404558,  DOI: 10.2174/0929867323666160907124013 .
        (b) Yared, J. A.; Tkaczuk, K. H. R. Update on taxane development: new analogues and new formulations. Drug Des., Dev. Ther. 2012, 6, 371384,  DOI: 10.2147/DDDT.S28997 .
        (c) Baker, A. F.; Dorr, R. T. Drug interactions with the taxanes: clinical implications. Cancer Treat. Rev. 2001, 27, 221233,  DOI: 10.1053/ctrv.2001.0228
      88. 88
        (a) Ishiyama, T.; Iimura, S.; Ohsuki, S.; Uoto, K.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Bioorg. Med. Chem. Lett. 2002, 12, 10831086,  DOI: 10.1016/S0960-894X(02)00069-0 .
        (b) Ishiyama, T.; Iimura, S.; Yoshino, T.; Chiba, J.; Uoto, K.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 2. Bioorg. Med. Chem. Lett. 2002, 12, 28152819,  DOI: 10.1016/S0960-894X(02)00628-5 .
        (c) Takeda, Y.; Yoshino, T.; Uoto, K.; Chiba, J.; Ishiyama, T.; Iwahana, M.; Jimbo, T.; Tanaka, N.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 3. Bioorg. Med. Chem. Lett. 2003, 13, 185190,  DOI: 10.1016/S0960-894X(02)00891-0 .
        (d) Takeda, Y.; Uoto, K.; Iwahana, M.; Jimbo, T.; Nagata, M.; Atsumi, R.; Ono, C.; Tanaka, N.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 5. Bioorg. Med. Chem. Lett. 2004, 14, 32093215,  DOI: 10.1016/j.bmcl.2004.03.109 .
        (e) Takeda, Y.; Uoto, K.; Chiba, J.; Horiuchi, T.; Iwahana, M.; Atsumi, R.; Ono, C.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 4. Bioorg. Med. Chem. 2003, 11, 44314447,  DOI: 10.1016/S0968-0896(03)00454-1 .
        (f) Shionoya, M.; Jimbo, T.; Kitagawa, M.; Soga, T.; Tohgo, A. DJ-927, a novel oral taxane, overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivo. Cancer Sci. 2003, 94, 459466,  DOI: 10.1111/j.1349-7006.2003.tb01465.x .
        (g) Ono, C.; Takao, A.; Atsumi, R. Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys. Biol. Pharm. Bull. 2004, 27, 345351,  DOI: 10.1248/bpb.27.345 .
        (h) Roche, M.; Kyriakou, H.; Seiden, M. Drug evaluation: tesetaxel - an oral semisynthetic taxane derivative. Curr. Opin. Investig. Drugs 2006, 7, 10921099.
        (i) Baas, P.; Szczesna, A.; Albert, I.; Milanowski, J.; Juhasz, E.; Sztancsik, Z.; von Pawel, J.; Oyama, R.; Burgers, S. Phase I/II study of a 3 weekly oral taxane (DJ-927) in patients with recurrent, advanced non-small cell lung cancer. J. Thorac. Oncol. 2008, 3, 745750,  DOI: 10.1097/JTO.0b013e31817c73ff .
        (j) Al Idrus, A. Odonate abandons breast cancer chemo drug, closes its doors. https://www.fiercebiotech.com/biotech/odonate-abandons-breast-cancer-chemo-drug-closes-its-doors (accessed March 22, 2021).
      89. 89
        (a) Sakya, S. M.; Bertinato, P.; Pratt, B.; Suarez-Contreras, M.; Lundy, K. M.; Minich, M. L.; Cheng, H.; Ziegler, C. B.; Kamicker, B. J.; Hayashi, S. F.; Santoro, S. L.; George, D. W.; Bertsche, C. D. Azalide 3,6-ketals: antibacterial activity and structure-activity relationships of aryl and hetero aryl substituted analogues. Bioorg. Med. Chem. Lett. 2003, 13, 13731375,  DOI: 10.1016/S0960-894X(03)00100-8 .
        (b) Cheng, H.; Dirlam, J. P.; Ziegler, C. B.; Lundy, K. M.; Hayashi, S. F.; Kamicker, B. J.; Dutra, J. K.; Daniel, K. L.; Santoro, S. L.; George, D. M.; Bertsche, C. D.; Sakya, S. M.; Suarez-Contreras, M. Synthesis and SAR of azalide 3,6-ketal aromatic derivatives as potent Gram-positive and Gram-negative antibacterial agents. Bioorg. Med. Chem. Lett. 2002, 12, 24312434,  DOI: 10.1016/S0960-894X(02)00434-1
      90. 90
        Wu, Y.-J. Highlights of semi-synthetic developments from erythromycin A. Curr. Pharm. Des. 2000, 6, 181223,  DOI: 10.2174/1381612003401316
      91. 91
        (a) Luke, D. R.; Foulds, G. Disposition of oral azithromycin in humans. Clin. Pharmacol. Ther. 1997, 61, 641648,  DOI: 10.1016/S0009-9236(97)90098-9 .
        (b) Lode, H.; Borner, K.; Koeppe, P.; Schaberg, T. Azithromycin-review of key chemical, pharmacokinetic and microbiological features. J. Antimicrob. Chemother. 1996, 37, 18,  DOI: 10.1093/jac/37.suppl_C.1 .
        (c) Allin, D.; James, I.; Zachariah, J.; Carr, W.; Cullen, S.; Middleton, A.; Newson, P.; Lytle, T.; Coles, S. Comparison of once- and twice-daily clarithromycin in the treatment of adults with severe acute lower respiratory tract infections. Clin. Ther. 2001, 23, 19581968,  DOI: 10.1016/S0149-2918(01)80149-1
      92. 92
        Botelho, A. F. M.; Pierezan, F.; Soto-Blanco, B.; Melo, M. M. A review of cardiac glycosides: structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potential. Toxicon 2019, 158, 6368,  DOI: 10.1016/j.toxicon.2018.11.429
      93. 93
        (a) Cohen, A.; Kroon, R.; Schoemaker, H.; Breimer, D.; Vliet-Verbeek, A.; Brandenburg, H. The bioavailability of digoxin from three oral formulations measured by a specific HPLC assay. Br. J. Clin. Pharmacol. 1993, 35, 136142,  DOI: 10.1111/j.1365-2125.1993.tb05679.x .
        (b) Peters, U.; Falk, L. C.; Kalman, S. M. Digoxin metabolism in patients. Arch. Intern. Med. 1978, 138, 10741076,  DOI: 10.1001/archinte.1978.03630320018009
      94. 94
        (a) Cowie, M. R.; Fisher, M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat. Rev. Cardiol. 2020, 17, 761772,  DOI: 10.1038/s41569-020-0406-8 .
        (b) Moradi-Marjaneh, R.; Paseban, M.; Sahebkar, A. Natural products with SGLT2 inhibitory activity: possibilities of application for the treatment of diabetes. Phytother. Res. 2019, 33, 25182530,  DOI: 10.1002/ptr.6421 .
        (c) Mariadoss, A. V. A.; Vinyagam, R.; Rajamanickam, V.; Sankaran, V.; Venkatesan, S.; David, E. Pharmacological aspects and potential use of phloretin: a systemic review. Mini-Rev. Med. Chem. 2019, 19, 10601067,  DOI: 10.2174/1389557519666190311154425
      95. 95
        Tsujihara, K.; Hongu, M.; Saito, K.; Kawanishi, H.; Kuriyama, K.; Matsumoto, M.; Oku, A.; Ueta, K.; Tsuda, M.; Saito, A. Na+-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4′-dehydroxyphlorizin derivatives substituted on the B ring. J. Med. Chem. 1999, 42, 53115324,  DOI: 10.1021/jm990175n
      96. 96
        Kees, K. L.; Fitzgerald, J. J., Jr.; Steiner, K. E.; Mattes, J. F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and -pyrazolones. J. Med. Chem. 1996, 39, 39203928,  DOI: 10.1021/jm960444z
      97. 97
        (a) Washburn, W. N. Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2. J. Med. Chem. 2009, 52, 17851794,  DOI: 10.1021/jm8013019 .
        (b) Choi, C.-I. Sodium-glucose cotransporter 2 (SGLT2) inhibitors from natural products: discovery of next-generation antihyperglycemic agents. Molecules 2016, 21, 1136,  DOI: 10.3390/molecules21091136
      98. 98
        (a) Shimizu, K.; Fujikura, H.; Fushimi, N.; Nishimura, T.; Tatani, K.; Katsuno, K.; Fujimori, Y.; Watanabe, S.; Hiratochi, M.; Nakabayashi, T.; Kamada, N.; Arakawa, K.; Hikawa, H.; Azumaya, I.; Isaji, M. Discovery of remogliflozin etabonate: A potent and highly selective SGLT2 inhibitor. Bioorg. Med. Chem. 2021, 34, 116033,  DOI: 10.1016/j.bmc.2021.116033 .
        (b) Sigafoos, J. F.; Bowers, G. D.; Castellino, S.; Culp, A. G.; Wagner, D. S.; Reese, M. J.; Humphreys, J. E.; Hussey, E. K.; O’Connor Semmes, R. L.; Kapur, A.; Tao, W.; Dobbins, R. L.; Polli, J. Assessment of the drug interaction risk for remogliflozin etabonate, a sodium-dependent glucose cotransporter-2 inhibitor: evidence from in vitro, human mass balance, and ketoconazole interaction studies. Drug Metab. Dispos. 2012, 40, 20902101,  DOI: 10.1124/dmd.112.047258 .
        (c) Kapur, A.; O’Connor-Semmes, R.; Hussey, E. K.; Dobbins, R. L.; Tao, W.; Hompesch, M.; Smith, G. A.; Polli, J. W.; James, C. D. Jr.; Mikoshiba, I.; Nunez, D. J. First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus. BMC Pharmacol. Toxicol. 2013, 14, 26,  DOI: 10.1186/2050-6511-14-26
      99. 99
        (a) Mohan, V.; Mithal, A.; Joshi, S. R.; Aravind, S. R.; Chowdhury, S. Remogliflozin etabonate in the treatment of type 2 diabetes: design, development, and place in therapy. Drug Des., Dev. Ther. 2020, 14, 24872501,  DOI: 10.2147/DDDT.S221093 .
        (b) Markham, A. Remogliflozin etabonate: first global approval. Drugs 2019, 79, 11571161,  DOI: 10.1007/s40265-019-01150-9
      100. 100
        Ting, H. J.; Murad, J. P.; Espinosa, E. V. P.; Khasawneh, F. T. Thromboxane A2 receptor: biology and function of a peculiar receptor that remains resistant for therapeutic targeting. J. Cardiovasc. Pharmacol. Ther. 2012, 17, 248259,  DOI: 10.1177/1074248411424145
      101. 101
        (a) Fried, J.; John, V.; Szwedo, M. J., Jr.; Chen, C.; O’Yang, C.; Morinelli, T. A.; Okwu, A. K.; Halushka, P. V. Synthesis of 10,10-difluorothromboxane A2, a potent and chemically stable thromboxane agonist. J. Am. Chem. Soc. 1989, 111, 45104511,  DOI: 10.1021/ja00194a062 .
        (b) Morinelli, T. A.; Okwu, A. K.; Mais, D. E.; Halushka, P. V.; John, V.; Chen, C. K.; Fried, J. Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels. Proc. Natl. Acad. Sci. U. S. A. 1989, 86, 56005604,  DOI: 10.1073/pnas.86.14.5600 .
        (c) Jing, C.; Mallah, S.; Kriemen, E.; Bennett, S. H.; Fasano, V.; Lennox, A. J.; Hers, I.; Aggarwal, V. K. Synthesis, stability, and biological studies of fluorinated analogues of thromboxane A2. ACS Cent. Sci. 2020, 6, 9951000,  DOI: 10.1021/acscentsci.0c00310 .
        (d) Schaaf, T. R.; Bussolotti, D. L.; Parry, M. J.; Corey, E. J. Synthesis of 11a,9a-epoxymethanothromboxane A2: a stable, optically active TxA2 agonist. J. Am. Chem. Soc. 1981, 103, 65026505,  DOI: 10.1021/ja00411a044
      102. 102
        (a) Longridge, J. L.; Nicholson, S. The alkaline stability of (5Z)-7-([2RS,4RS,5SR]-4-o-hydroxyphenyl-2-trifluoromethyl-1,3-dioxan-5-yl)hept-5-enoic acid, ICI 185282. A remarkable intramolecular hydride transfer from a trifluoromethyl substituted carbon atom. J. Chem. Soc., Perkin Trans. 2 1990, 965970,  DOI: 10.1039/p29900000965 .
        (b) Brewster, A. G.; Brown, G. R.; Foubister, A. J.; Jessup, R.; Smithers, M. J. The synthesis of a novel thromboxane receptor antagonist 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl) hexenoic acid ICI 192605. Prostaglandins 1988, 36, 173178,  DOI: 10.1016/0090-6980(88)90304-8
      103. 103
        (a) O’Neill, P. M.; Posner, G. H. A medicinal chemistry perspective on artemisinin and related endoperoxides. J. Med. Chem. 2004, 47, 29452964,  DOI: 10.1021/jm030571c .
        (b) Krishna, S.; Bustamante, L.; Haynes, T. K.; Staines, H. M. Artemisinins: their growing importance in medicine. Trends Pharmacol. Sci. 2008, 29, 520527,  DOI: 10.1016/j.tips.2008.07.004
      104. 104
        (a) Ilett, K. F.; Ethell, B. T.; Maggs, J. L.; Davis, D. M. E.; Batty, K. T.; Burchell, B.; Binh, T. W.; Thu, L. T.; Hung, N. C.; Pirmohamed, M.; Park, B. K.; Edwards, G. Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab. Dispos. 2002, 30, 10051012,  DOI: 10.1124/dmd.30.9.1005 .
        (b) O’Neill, P. M.; Scheinmann, F.; Stachulski, A. V.; Maggs, J. L.; Park, B. K. Efficient preparations of the α-glucuronides of dihydroartemisinin and structural confirmation of the human glucuronide metabolite. J. Med. Chem. 2001, 44, 14671470,  DOI: 10.1021/jm001061a
      105. 105
        (a) Nga, T. T. T.; Menage, C.; Begue, J.-P.; Bonnet-Delpon, D.; Gantier, J.-C.; Pradines, B.; Doury, J.-C.; Thac, T. D. Synthesis and antimalarial activities of fluoroalkyl derivatives of dihydroartemisinin. J. Med. Chem. 1998, 41, 41014108,  DOI: 10.1021/jm9810147 .
        (b) Magueur, G.; Crousse, B.; Charneau, S.; Grellier, P.; Begue, J.-P.; Bonnet-Delpon, D. Fluoroartemisinin: trifluoromethyl analogues of artemether and artesunate. J. Med. Chem. 2004, 47, 26942699,  DOI: 10.1021/jm0310333 .
        (c) Bgu, J.-P.; Bonnet-Delpon, D. Antimalarial fluoroartimisinins: increased metabolic and chemical stability. Fluorine in Medicinal Chemistry and Chemical Biology 2009, 141163,  DOI: 10.1002/9781444312096.ch6 .
        (d) Njokah, M. J.; Kang’ethe, J. N.; Kinyua, J.; Kariuki, D.; Kimani, F. T. In vitro selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemisinin. Malar. J. 2016, 15, 381,  DOI: 10.1186/s12936-016-1443-y
      106. 106
        Elkeles, R. Fibrates: old drugs with a new role in type 2 diabetes prevention?. Br. J. Diabetes Vasc. Dis. 2011, 11, 49,  DOI: 10.1177/1474651410397245
      107. 107
        Pirat, C.; Farce, A.; Lebegue, N.; Renault, N.; Furman, C.; Millet, R.; Yous, S.; Speca, S.; Berthelot, P.; Desreumaux, P.; Chavatte, P. Targeting peroxisome proliferator-activated receptors (PPARs): development of modulators. J. Med. Chem. 2012, 55, 40274061,  DOI: 10.1021/jm101360s
      108. 108
        (a) Asaki, T.; Aoki, T.; Hamamoto, T.; Sugiyama, Y.; Ohmachi, S.; Kuwabara, K.; Murakami, K.; Todo, M. Structure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor δ. (PPARα) agonists. Bioorg. Med. Chem. 2008, 16, 981994,  DOI: 10.1016/j.bmc.2007.10.007 .
        (b) Aoki, T.; Asaki, T.; Hamamoto, T.; Sugiyama, Y.; Ohmachi, S.; Kuwabara, K.; Murakami, K.; Todo, M. Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor δ (PPARα) agonists. Bioorg. Med. Chem. Lett. 2008, 18, 21282132,  DOI: 10.1016/j.bmcl.2008.01.086
      109. 109
        (a) Tschierske, C.; Kshler, H.; Zaschke, H.; Kleinpete, E. The anomeric effect of the carboethoxy group in oxygen and sulfur containing heterocycles. Tetrahedron 1989, 45, 69876998,  DOI: 10.1016/S0040-4020(01)89165-1 .
        (b) Harabe, T.; Matsumoto, T.; Shioiri, T. Conformational analysis and selective hydrolysis of 2,5-disubstituted-1,3-dioxane-2-carboxylic acid esters. Tetrahedron Lett. 2007, 48, 14431446,  DOI: 10.1016/j.tetlet.2006.12.117 .
        (c) Harabe, T.; Matsumoto, T.; Shioiri, T. Esters of 2,5-multisubstituted-1,3-dioxane-2-carboxylic acid: their conformational analysis and selective hydrolysis. Tetrahedron 2009, 65, 40444052,  DOI: 10.1016/j.tet.2009.02.076
      110. 110
        (a) Zaware, P.; Shah, S. R.; Pingali, H.; Makadia, P.; Thube, B.; Pola, S.; Patel, D.; Priyadarshini, P.; Suthar, D.; Shah, M.; Jamili, J.; Sairam, K. V.; Giri, S.; Patel, L.; Patel, H.; Sudani, H.; Patel, H.; Jain, M.; Patel, P.; Bahekar, R. Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/δ dual agonist into a selective PPAR agonist through bioisosteric modification. Bioorg. Med. Chem. Lett. 2011, 21, 628632,  DOI: 10.1016/j.bmcl.2010.12.032 .
        (b) Pingali, H.; Jain, M.; Shah, S.; Patil, P.; Makadia, P.; Zaware, P.; Sairam, K. V.; Jamili, J.; Goel, A.; Patel, M.; Patel, P. Modulation of PPAR receptor subtype selectivity of the ligands: Aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety. Bioorg. Med. Chem. Lett. 2008, 18, 64716475,  DOI: 10.1016/j.bmcl.2008.10.062
      111. 111
        LeMahieu, R. A.; Carson, M.; Kierstead, R. W.; Fern, L. M.; Grunberg, E. Glycoside cleavage reactions on erythromycin A. Preparation of erythronolide A. J. Med. Chem. 1974, 17, 953956,  DOI: 10.1021/jm00255a009
      112. 112
        (a) Martin, R.; Plancq, B.; Gavelle, O.; Wagner, B.; Fischer, H.; Bendels, S.; Müller, K. Remote modulation of amine basicity by a phenylsulfone and a phenylthio group. ChemMedChem 2007, 2, 285287,  DOI: 10.1002/cmdc.200600265 .
        (b) Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 11001115,  DOI: 10.1002/cmdc.200700059
      113. 113
        Lenci, E.; Calugi, L.; Trabocchi, A. Occurrence of morpholine in central nervous system drug discovery. ACS Chem. Neurosci. 2021, 12, 378390,  DOI: 10.1021/acschemneuro.0c00729
      114. 114
        (a) Hale, J. L.; Mills, S. G.; MacCoss, M.; Shah, S. K.; Qi, H.; Mathre, D. J.; Cascieri, M. A.; Sadowski, S.; Strader, C. D.; MacIntyre, D. E.; Metzger, J. M. 2(S)-((3,5-Bis(trifluoromethyl)benzyl)-oxy)-3(S)-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine (1): a potent, orally active, morpholine-based human neurokinin-1 receptor antagonist. J. Med. Chem. 1996, 39, 17601762,  DOI: 10.1021/jm950654w .
        (b) Ladduwahetty, T.; Baker, R.; Cascieri, M. A.; Chambers, M. S.; Haworth, K.; Keown, L. E.; MacIntyre, D. E.; Metzger, J. M.; Owen, S.; Rycroft, W.; Sadowski, S.; Seward, E. M.; Shepheard, S. L.; Swain, C. J.; Tattersall, F. D.; Watt, A. P.; Williamson, D. W.; Hargreaves, R. J. N-Heteroaryl-2-phenyl-3-(benzyloxy)piperidines: a novel class of potent orally active human NK1 antagonists. J. Med. Chem. 1996, 39, 29072914,  DOI: 10.1021/jm9506534 .
        (c) Chen, S.; Lu, M.; Liu, D.; Yang, L.; Yi, C.; Ma, L.; Zhang, H.; Liu, Q.; Frimurer, T. M.; Wang, M.-W.; Schwartz, T. W.; Stevens, R. C.; Wu, B.; Wüthrich, K.; Zhao, Q. Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography. Nat. Commun. 2019, 10, 638,  DOI: 10.1038/s41467-019-08568-5 .
        (d) Gangula, S.; Elati, C. R.; Mudunuru, S. V.; Nardela, A.; Dongamanti, A.; Bhattacharya, A.; Bandichhor, R. Synthesis of all enantiomerically pure diastereomers of aprepitant. Synth. Commun. 2010, 40, 22542268,  DOI: 10.1080/00397910903221084
      115. 115
        Hale, J. J.; Mills, S. G.; MacCoss, M.; Dorn, C. P.; Finke, P. E.; Budhu, R. J.; Reamer, R. A.; Huskey, S. W.; Luffer-Atlas, D.; Dean, B. J.; McGowan, E. M.; Feeney, W. P.; Chiu, S. L.; Cascieri, M. A.; Chicchi, G. G.; Kurtz, M. M.; Sadowski, S.; Ber, E.; Tattersall, F. D.; Rupniak, N. M.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; Metzger, J. M.; MacIntyre, D. E. Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. J. Med. Chem. 2000, 43, 12341241,  DOI: 10.1021/jm990617v
      116. 116
        (a) Fuller, N. O.; Hubbs, J. J.; Austin, W. F.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M.; Tate, B.; Xia, W.; Ives, J. L.; Findeis, M. A.; Bronk, B. S. Initial optimization of a new series of γ-secretase modulators derived from a triterpene glycoside. ACS Med. Chem. Lett. 2012, 3, 908913,  DOI: 10.1021/ml300256p .
        (b) Hubbs, J. L.; Fuller, N. O.; Austin, W. F.; Shen, R.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M.; Tate, B.; Xia, W.; Ives, J.; Bronk, B. S. Optimization of a natural product-based class of γ-secretase modulators. J. Med. Chem. 2012, 55, 92709282,  DOI: 10.1021/jm300976b .
        (c) Loureiro, R. M.; Dumin, J. A.; McKee, T. D.; Austin, W. F.; Fuller, N. O.; Hubbs, J. L.; Shen, R.; Jonker, J.; Ives, J.; Bronk, B. S.; Tate, B. Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models. Alzheimer's Res. Ther. 2013, 5, 19,  DOI: 10.1186/alzrt173 .
        (d) Fuller, N. O.; Hubbs, J. L.; Austin, W. F.; Shen, R.; Ives, J.; Osswald, G.; Bronk, B. S. Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ-Secretase Modulator. Org. Process Res. Dev. 2014, 18, 683692,  DOI: 10.1021/op500072b
      117. 117
        (a) Kaneko, S.; Arai, M.; Uchida, T.; Harasaki, T.; Fukuoka, T.; Konosu, T. Synthesis and evaluation of N-substituted 1,4-oxazepanyl sordaricins as selective fungal EF-2 inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 17051708,  DOI: 10.1016/S0960-894X(02)00290-1 .
        (b) Arai, M.; Harasaki, T.; Fukuoka, T.; Kaneko, S.; Konosu, T. Synthesis and evaluation of novel pyrrolidinyl sordaricin derivatives as antifungal agents. Bioorg. Med. Chem. Lett. 2002, 12, 27332736,  DOI: 10.1016/S0960-894X(02)00534-6 .
        (c) Serrano-Wu, M. H.; St. Laurent, D. R.; Chen, Y.; Huang, S.; Lam, K.-R.; Matson, J. A.; Mazzucco, C. E.; Stickle, T. M.; Tully, T. P.; Wong, H. S.; Vyas, D. M.; Balasubramanian, B. N. Sordarin oxazepine derivatives as potent antifungal agents. Bioorg. Med. Chem. Lett. 2002, 12, 27572760,  DOI: 10.1016/S0960-894X(02)00529-2 .
        (d) Serrano-Wu, M. H.; Laurent, D. R.S..; Carroll, T. M.; Dodier, M.; Gao, Q.; Gill, P.; Quesnelle, C.; Marinier, A.; Mazzucco, C. E.; Regueiro-Ren, A.; Stickle, T. M.; Wu, D.; Yang, H.; Yang, Z.; Zheng, M.; Zoeckler, M. E.; Vyas, D. M.; Balasubramanian, B. N. Identification of a broad-spectrum azasordarin with improved pharmacokinetic properties. Bioorg. Med. Chem. Lett. 2003, 13, 14191423,  DOI: 10.1016/S0960-894X(03)00161-6 .
        (e) Kamai, Y.; Kakuta, M.; Shibayama, T.; Fukuoka, T.; Kuwahara, S. Antifungal activities of R-135853, a sordarin derivative, in experimental candidiasis in mice. Antimicrob. Agents Chemother. 2005, 49, 5256,  DOI: 10.1128/AAC.49.1.52-56.2005
      118. 118
        Bueno, A. B.; Agejas, J.; Broughton, H.; Dally, R.; Durham, T. B.; Espinosa, J. F.; Gonzalez, R.; Hahn, P. J.; Marcos, A.; Rodríguez, R.; Sanz, G.; Soriano, J. F.; Timm, D.; Vidal, P.; Yang, H.; McCarthy, J. R. Optimization of hydroxyethylamine transition state isosteres as aspartic protease inhibitors by exploiting conformational preferences. J. Med. Chem. 2017, 60, 98079820,  DOI: 10.1021/acs.jmedchem.7b01304
      119. 119
        (a) Eliel, E. I.; Alcudia, F. Acetylcholine analogues. Conformational equilibriums dominated by electrostatic interactions. J. Am. Chem. Soc. 1974, 96, 19391941,  DOI: 10.1021/ja00813a051 .
        (b) Kaloustian, M. K.; Dennis, N.; Mager, S.; Evans, S. A.; Alcudia, F.; Eliel, E. I. Conformational analysis. XXXI. Conformational equilibria of 1,3-dioxanes with polar substituents at C-5. J. Am. Chem. Soc. 1976, 98, 956965,  DOI: 10.1021/ja00420a015
      120. 120
        Pasternak, A.; Pan, Y.; Marino, D.; Sanderson, P. E.; Mosley, R.; Rohrer, S. P.; Birzin, E. T.; Huskey, S. W.; Jacks, T.; Schleim, K. D.; Cheng, K.; Schaeffer, J. M.; Patchett, A. A.; Yang, L. Potent, orally bioavailable somatostatin agonists: good absorption achieved by urea backbone cyclization. Bioorg. Bioorg. Med. Chem. Lett. 1999, 9, 491496,  DOI: 10.1016/S0960-894X(99)00016-5
      121. 121
        (a) Li, L.; Okumu, A.; Dellos-Nolan, S.; Li, Z.; Karmahapatra, S.; English, A.; Yalowich, J. C.; Wozniak, D. J.; Mitton-Fry, M. J. Synthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moiety. Bioorg. Med. Chem. Lett. 2018, 28, 24772480,  DOI: 10.1016/j.bmcl.2018.06.003 .
        (b) Lu, Y.; Papa, J. L.; Nolan, S.; English, A.; Seffernick, J. T.; Shkolnikov, N.; Powell, J.; Lindert, S.; Wozniak, D. J.; Yalowich, J.; Mitton-Fry, M. J. Dioxane-linked amide derivatives as novel bacterial topoisomerase inhibitors against Gram-positive Staphylococcus aureus. ACS Med. Chem. Lett. 2020, 11, 24462454,  DOI: 10.1021/acsmedchemlett.0c00428
      122. 122
        Kemp, J. A.; Keebaugh, A.; Edson, J. A.; Chow, D.; Kleinman, M. T.; Chew, Y. C.; McCracken, A. N.; Edinger, A. L.; Kwon, Y. J. Biocompatible chemotherapy for leukemia by acid-cleavable, PEGylated FTY720. Bioconjugate Chem. 2020, 31, 673684,  DOI: 10.1021/acs.bioconjchem.9b00822
      123. 123
        Kirby, A. J.; Percy, J. M. Intramolecular proton-transfer catalysis of nucleophilic catalysis of acetal hydrolysis. The hydrolysis of 8-dimethylamino-1-methoxymethoxynaphthalene. J. Chem. Soc., Perkin Trans. 2 1989, 907912,  DOI: 10.1039/p29890000907
      124. 124
        (a) Bi, L.; Zhao, M.; Gu, K.; Wang, C.; Ju, J.; Peng, S. Toward the development of chemoprevention agents (III): Synthesis and anti-inflammatory activities of a new class of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes. Bioorg. Med. Chem. 2008, 16, 17641774,  DOI: 10.1016/j.bmc.2007.11.017 .
        (b) Bi, L.; Zhang, Y.; Zhao, M.; Wang, C.; Chan, P.; Tok, J. B.-H.; Peng, S. Novel synthesis and anti-inflammatory activities of 2,5-disubstituted-dioxacycloalkanes. Bioorg. Med. Chem. 2005, 13, 56405646,  DOI: 10.1016/j.bmc.2005.05.032
      125. 125
        (a) Dovgan, I.; Kolodych, S.; Koniev, O.; Wagner, A. 2-(Maleimidomethyl)-1,3-dioxanes (MD): a serum-stable self-hydrolysable hydrophilic alternative to classical maleimide conjugation. Sci. Rep. 2016, 6, 30835,  DOI: 10.1038/srep30835 .
        (b) Tobaldi, E.; Dovgan, I.; Mosser, M.; Becht, J.-M.; Wagner, A. Structural investigation of cyclo-dioxo maleimide cross-linkers for acid and serum stability. Org. Biomol. Chem. 2017, 15, 93059310,  DOI: 10.1039/C7OB01757J
      126. 126
        Maertens, J. A. History of the development of azole derivatives. Clin. Microbiol. Infect. 2004, 10, 110,  DOI: 10.1111/j.1470-9465.2004.00841.x
      127. 127
        Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. Antimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent. J. Med. Chem. 1979, 22, 10031005,  DOI: 10.1021/jm00194a023
      128. 128
        (a) Vanden Bossche, H.; Heeres, J.; Backx, L. J. J.; Marichal, P.; Willemsens, G. Discovery, chemistry, mode of action, and selectivity of itraconazole. In Cutaneus Antifungal Agents; Rippon, J. W., Fromtling, R. A., Eds.; Marcel Decker Inc.: New York, 1993; pp 263283.
        (b) Martin, M. V. The use of fluconazole and itraconazole in the treatment of Candida albicans infections: a review. J. Antimicrob. Chemother. 1999, 44, 429437,  DOI: 10.1093/jac/44.4.429
      129. 129
        Fukami, T.; Iida, A.; Konishi, K.; Nakajima, M. Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicity. Biochem. Pharmacol. 2016, 116, 153161,  DOI: 10.1016/j.bcp.2016.07.007
      130. 130
        (a) Niwa, T.; Imagawa, Y.; Yamazaki, H. Drug interactions between nine antifungal agents and drugs metabolized by human cytochromes P450. Curr. Drug Metab. 2015, 15, 651679,  DOI: 10.2174/1389200215666141125121511 .
        (b) Khojasteh, S. C.; Prabhu, S.; Kenny, J. R.; Halladay, J. S.; Lu, A. Y. H. Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity. Eur. J. Drug Metab. Pharmacokinet. 2011, 36, 116,  DOI: 10.1007/s13318-011-0024-2
      131. 131
        (a) Van Tyle, J. H. Ketoconazole; Mechanism of action, spectrum of activity, pharmacokinetics, drug interactions, adverse reactions and therapeutic use. Pharmacotherapy 1984, 4, 343373,  DOI: 10.1002/j.1875-9114.1984.tb03398.x .
        (b) Rodriguez, R. J.; Acosta, D., Jr. Metabolism of ketoconazole and deacetylated ketoconazole by rat hepatic microsomes and flavin-containing monooxygenases. Drug Metab. Dispos. 1997, 25, 772777
      132. 132
        (a) Poirier, J. M.; Lebot, M.; Descamps, P.; Levy, M.; Cheymol, G. Determination of itraconazole and its active metabolite in plasma by column liquid chromatography. Ther. Drug Monit. 1994, 16, 596601,  DOI: 10.1097/00007691-199412000-00011 .
        (b) Peng, C. C.; Shi, W.; Lutz, J. D.; Kunze, K. L.; Liu, J. O.; Nelson, W. L.; Isoherranen, N. Stereospecific metabolism of itraconazole by CYP3A4: dioxolane ring scission of azole antifungals. Drug Metab. Dispos. 2012, 40, 426435,  DOI: 10.1124/dmd.111.042739
      133. 133
        (a) Sawyer, P. R.; Brogden, R. N.; Pinder, R. M.; Speight, T. M.; Avery, G. S. Miconazole: review of its antifungal activity and therapeutic efficacy. Drugs 1975, 9, 406423,  DOI: 10.2165/00003495-197509060-00002 .
        (b) Fothergill, A. W. Miconazole: a historical perspective. Expert Rev. Anti-Infect. Ther. 2006, 4, 171175,  DOI: 10.1586/14787210.4.2.171
      134. 134
        Godefroi, E. F.; Heeres, J.; Van Cutsem, J.; Janssen, P. A. J. The preparation and antimycotic properties of derivatives of 1-phenethylimidazole. J. Med. Chem. 1969, 12, 784791,  DOI: 10.1021/jm00305a014
      135. 135
        Heeres, J.; Van Cutsem, J. Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles. J. Med. Chem. 1981, 24, 13601364,  DOI: 10.1021/jm00143a019
      136. 136
        Heeres, J.; Meerpoel, L.; Lewi, P. Conazoles. Molecules 2010, 15, 41294188,  DOI: 10.3390/molecules15064129
      137. 137
        Lewis, D. F.; Wiseman, A.; Tarbit, M. H. Molecular modelling of lanosterol 14α-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform: quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivatives. J. Enzyme Inhib. 1999, 14, 175192,  DOI: 10.3109/14756369909030315
      138. 138
        (a) Collis, A. J.; Foster, M. L.; Halley, F.; Maslen, C.; McLay, I. M.; Page, K. M.; Redford, E. J.; Souness, J. E.; Wilsher, N. E. RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency. Bioorg. Med. Chem. Lett. 2001, 11, 693696,  DOI: 10.1016/S0960-894X(01)00034-8 .
        (b) McKenna, J. M.; Halley, F.; Souness, J. E.; McLay, I. M.; Pickett, S. D.; Collis, A. J.; Page, K.; Ahmed, I. An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors. J. Med. Chem. 2002, 45, 21732184,  DOI: 10.1021/jm011132l
      139. 139
        (a) Abbotto, A.; Bradamante, S.; Pagani, G. A. Diheteroarylmethanes. 5.1 E-Z isomerism of carbanions substituted by 1,3-azoles: 13C and 15N δ-charge/shift relationships as source for mapping charge and ranking the electron-withdrawing power of heterocycles. J. Org. Chem. 1996, 61, 17611769,  DOI: 10.1021/jo951884l .
        (b) Abbotto, A.; Bradamante, S.; Facchetti, A.; Pagani, G. A. Metal chelation aptitudes of bis(o-azaheteroaryl)methanes as tuned by heterocycle charge demands. J. Org. Chem. 2002, 67, 57535772,  DOI: 10.1021/jo025696o
      140. 140
        Collis, A.; Halley, F.; McClay, I. Heteroaryl-cyclic acetals. U.S. Patent 7,479,501 B2. January 30th, 2009.
      141. 141
        (a) Lovering, F. Escape from flatland 2: complexity and promiscuity. MedChemComm 2013, 4, 515519,  DOI: 10.1039/c2md20347b .
        (b) Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson, J. A.; Shamji, A. F.; Wagner, B. K.; Koehler, A. N.; Schreiber, S. L. Small molecules of different synthetic and natural origins have distinct distributions of structural complexity that correlate with protein binding profiles. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 1878718792,  DOI: 10.1073/pnas.1012741107 .
        (c) Meanwell, N. A. Improving drug design: an update on recent applications of efficiency metrics, strategies for replacing problematic elements, and compounds in nontraditional drug space. Chem. Res. Toxicol. 2016, 29, 564616,  DOI: 10.1021/acs.chemrestox.6b00043
      142. 142
        Astles, P. C.; Ashton, M. J.; Bridge, A. W.; Harris, N. V.; Hart, T. W.; Parrott, D. P.; Porter, B.; Riddell, D.; Smith, C.; Williams, R. J. Acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT. J. Med. Chem. 1996, 39, 14231432,  DOI: 10.1021/jm9505876
      143. 143
        (a) Dostertp, P.; Langlois, M.; Guerret, P.; Ancher, J. F.; Bucher, B.; Mocquet, G. Synthesis and pharmacological properties of analogues of oxapadol, a new analgesic agent. Eur. J. Med. Chem. 1980, 15, 199205.
        (b) Mocquet, G.; Coston, A.; Jalfre, M. Animal pharmacology of oxapadol (MD 720111), a new non-narcotic analgesic. Experientia 1980, 36, 9697,  DOI: 10.1007/BF02003996
      144. 144
        (a) Boureau, F.; Laquais, B.; Vadrot, M.; Willer, J.-C. Human neuropharmacological findings with oxapadol (MD 720111), a new non-narcotic analgesic. Experientia 1980, 36, 9798,  DOI: 10.1007/BF02003997 .
        (b) Ancher, J. F.; Donath, A.; Malnoe, A.; Morizur, J. P.; Strolin Bekedetti, M. Urinary metabolites of oxapadol (MD720111), a new non-narcotic analgesic agent, in the rat, dog and man. Xenobiotica 1981, 11, 519530,  DOI: 10.3109/00498258109045863
      145. 145
        Lenci, E.; Menchi, G.; Saldívar-Gonzalez, F.; Medina-Franco, J. L.; Trabocchi, A. Bicyclic acetals: biological relevance, scaffold analysis, and applications in diversity-oriented synthesis. Org. Biomol. Chem. 2019, 17, 10371052,  DOI: 10.1039/C8OB02808G
      146. 146
        (a) Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi, E.; Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.; Kimata, H.; Nakayama, K.; Tsuda-Tsukimoto, M. Discovery of canagliflozin, a novel c-glucoside with thiophene ring, as sodium-dependent glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J. Med. Chem. 2010, 53, 63556360,  DOI: 10.1021/jm100332n .
        (b) Lamos, E. M.; Younk, L. M.; Davis, S. N. Canagliflozin, an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin. Drug Metab. Toxicol. 2013, 9, 763775,  DOI: 10.1517/17425255.2013.791282
      147. 147
        (a) Meng, W.; Ellsworth, B. A.; Nirschl, A. A.; McCann, P. J.; Patel, M.; Girotra, R. N.; Wu, G.; Sher, P. M.; Morrison, E. P.; Biller, S. A.; Zahler, R. A.; Deshpande, P. P.; Pullockaran, A.; Hagan, D. L.; Morgan, N.; Taylor, J. R.; Obermeier, M. T.; Humphreys, W. G.; Khanna, A.; Discenza, L.; Robertson, J. G.; Wang, A.; Han, S.; Wetterau, J. R.; Janovitz, E. B.; Flint, O. P.; Whaley, J. M.; Washburn, W. N. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2008, 51, 11451149,  DOI: 10.1021/jm701272q .
        (b) Plosker, G. L. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs 2012, 72, 22892312,  DOI: 10.2165/11209910-000000000-00000
      148. 148
        Haider, K.; Pathak, A.; Rohilla, A.; Haider, M. R.; Ahmad, K.; Yar, M. S. Synthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: a review. Eur. J. Med. Chem. 2019, 184, 111773,  DOI: 10.1016/j.ejmech.2019.111773
      149. 149
        (a) Mascitti, V.; Maurer, T. S.; Robinson, R. P.; Bian, J.; Boustany-Kari, C. M.; Brandt, T.; Collman, B. M.; Kalgutkar, A. S.; Klenotic, M. K.; Leininger, M. T.; Lowe, A.; Maguire, R. J.; Masterson, V. M.; Miao, Z.; Mukaiyama, E.; Patel, J. D.; Pettersen, J. C.; Preville, C.; Samas, B.; She, L.; Sobol, Z.; Steppan, C. M.; Stevens, B. D.; Thuma, B. A.; Tugnait, M.; Zeng, D.; Zhu, T. Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors. J. Med. Chem. 2011, 54, 29522960,  DOI: 10.1021/jm200049r .
        (b) Mascitti, V.; Thuma, B. A.; Smith, A. C.; Robinson, R. P.; Brandt, T.; Kalgutkar, A. S.; Maurer, T. S.; Samas, B.; Sharma, R. On the importance of synthetic organic chemistry in drug discovery: reflections on the discovery of antidiabetic agent ertugliflozin. MedChemComm 2013, 4, 101111,  DOI: 10.1039/C2MD20163A
      150. 150
        (a) Miao, Z.; Nucci, G.; Amin, N.; Sharma, R.; Mascitti, V.; Tugnait, M.; Vaz, A. D.; Callegari, E.; Kalgutkar, A. S. Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab. Dispos. 2013, 41, 445456,  DOI: 10.1124/dmd.112.049551 .
        (b) Raje, S.; Callegari, E.; Sahasrabudhe, V.; Vaz, A.; Shi, H.; Fluhler, E.; Woolf, E. J.; Schildknegt, K.; Matschke, K.; Alvey, C.; Zhou, S.; Papadopoulos, D.; Fountaine, R.; Saur, D.; Terra, S. G.; Stevens, L.; Gaunt, D.; Cutler, D. L. Novel application of the two-period microtracer approach to determine absolute oral bioavailability and fraction absorbed of ertugliflozin. Clin. Transl. Sci. 2018, 11, 405411,  DOI: 10.1111/cts.12549 .
        (c) Fediuk, D. J.; Nucci, G.; Dawra, V. K.; Cutler, D. L.; Amin, N. B.; Terra, S. G.; Boyd, R. A.; Krishna, R.; Sahasrabudhe, V. Overview of the clinical pharmacology of ertugliflozin, a novel sodium-glucose cotransporter 2 (SGLT2) inhibitor. Clin. Pharmacokinet. 2020, 59, 949965,  DOI: 10.1007/s40262-020-00875-1
      151. 151
        Yan, Q.; Ding, N.; Li, Y. Synthesis and biological evaluation of novel dioxa-bicycle C-arylglucosides as SGLT2 inhibitors. Carbohydr. Res. 2016, 421, 18,  DOI: 10.1016/j.carres.2015.10.011
      152. 152
        Rendell, M. S. Sotagliflozin: a combined SGLT1/SGLT2 inhibitor to treat diabetes. Expert Rev. Endocrinol. Metab. 2018, 13, 333339,  DOI: 10.1080/17446651.2018.1537779
      153. 153
        Li, Y.; Shi, Z.; Chen, L.; Zheng, S.; Li, S.; Xu, B.; Liu, Z.; Liu, J.; Deng, C.; Ye, F. Discovery of a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (HSK0935) for the treatment of type 2 diabetes. J. Med. Chem. 2017, 60, 41734184,  DOI: 10.1021/acs.jmedchem.6b01818
      154. 154
        Wenzel, S. E.; Kamada, A. K. Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma. Ann. Pharmacother. 1996, 30, 858864,  DOI: 10.1177/106002809603000725
      155. 155
        (a) Delorme, D.; Ducharme, Y.; Brideau, C.; Chan, C. C.; Chauret, N.; Desmarais, S.; Dubé, D.; Falgueyret, J. P.; Fortin, R.; Guay, J.; Hamel, P.; Jones, T. R.; Lépine, C.; Li, C.; McAuliffe, M.; McFarlane, C. S.; Nicoll-Griffith, D. A.; Riendeau, D.; Yergey, J. A.; Girard, Y. Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: structure-activity relationship study directed toward the improvement of metabolic stability. J. Med. Chem. 1996, 39, 39513970,  DOI: 10.1021/jm960301c .
        (b) Hamel, P.; Riendeau, D.; Brideau, C.; Chan, C.-C.; Desmarais, S.; Delorme, D.; Dube, D.; Ducharme, Y.; Ethier, D.; Grimm, E.; Falgueyret, J.-P.; Guay, J.; Jones, T. R.; Kwong, E.; McFarlane, C. S.; Piechuta, H.; Roumi, M.; Tagari, P.; Young, R. N.; Girard, Y. Substituted (pyridylmethoxy)naphthalenes as potent and orally active 5-lipoxygenase inhibitor. synthesis, biological profile, and pharmacokinetics of L-739,010. J. Med. Chem. 1997, 40, 28662875,  DOI: 10.1021/jm970046b
      156. 156
        (a) Chauret, N.; Nicoll-Griffith, D.; Friesen, R.; Li, C.; Trimble, L.; Dubé, D.; Fortin, R.; Girard, Y.; Yergey, J. Microsomal metabolism of the 5-lipoxygenase inhibitors L-746,530 and L-739,010 to reactive intermediates that covalently bind to protein: the role of the 6,8-dioxabicyclo[3.2.1]octanyl moiety. Drug Metab. Dispos. 1995, 23, 13251334.
        (b) Zhang, K. E.; Naue, J. A.; Arison, B.; Vyas, K. P. Microsomal metabolism of the 5-lipoxygenase inhibitor L-739,010: evidence for furan bioactivation. Chem. Res. Toxicol. 1996, 9, 547554,  DOI: 10.1021/tx950183g
      157. 157
        Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.; Ahn, K.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. Discovery of tofogliflozin, a novel C-arylglucoside with an O-spiroketal ring system, as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2012, 55, 78287840,  DOI: 10.1021/jm300884k
      158. 158
        (a) Lv, B.; Xu, B.; Feng, Y.; Peng, K.; Xu, G.; Du, J.; Zhang, L.; Zhang, W.; Zhang, T.; Zhu, L.; Ding, H.; Sheng, Z.; Welihinda, A.; Seed, B.; Chen, Y. Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 68776881,  DOI: 10.1016/j.bmcl.2009.10.088 .
        (b) Kasahara-Ito, N.; Fukase, H.; Ogama, Y.; Saito, T.; Ohba, Y.; Shimada, S.; Takano, Y.; Ichihara, T.; Terao, K.; Nakamichi, N.; Kumagai, Y.; Ikeda, S. Pharmacokinetics and pharmacodynamics of tofogliflozin (a selective SGLT2 inhibitor) in healthy male subjects. Drug Res. 2017, 67, 349357,  DOI: 10.1055/s-0043-104779
      159. 159
        (a) Seward, E. M.; Carlson, E.; Harrison, T.; Haworth, K. E.; Herbert, R.; Kelleher, F. J.; Kurtz, M. M.; Moseley, J.; Owen, S. N.; Owens, A. P.; Sadowski, S. J.; Swain, C. J.; Williams, B. J. Spirocyclic NK1 antagonists I: [4.5] and [5.5]-spiroketals. Bioorg. Med. Chem. Lett. 2002, 12, 25152518,  DOI: 10.1016/S0960-894X(02)00506-1 .
        (b) Quach, R.; Furkert, D. P.; Brimble, M. A. Gold Catalysis: Synthesis of Spiro, Bridged, and Fused Ketal Natural Products. Org. Biomol. Chem. 2017, 15, 30983104,  DOI: 10.1039/C7OB00496F .
        (c) Choi, K. W.; Brimble, M. A. Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffolds. Org. Biomol. Chem. 2009, 7, 142436,  DOI: 10.1039/b818314g .
        (d) Zhang, F. M.; Zhang, S. Y.; Tu, Y. Q. Recent progress in the isolation, bioactivity, biosynthesis, and total synthesis of natural spiroketals. Nat. Prod. Rep. 2018, 35, 75104,  DOI: 10.1039/C7NP00043J .
        (e) Lenci, E. Synthesis and biological properties of spiroacetal-containing small molecules. Small Molecule Drug Discovery 2020, 225245,  DOI: 10.1016/B978-0-12-818349-6.00008-X
      160. 160
        (a) Ghosh, A. K.; Dawson, Z. L.; Mitsuya, H. Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV. Bioorg. Med. Chem. 2007, 15, 75767580,  DOI: 10.1016/j.bmc.2007.09.010 .
        (b) Ghosh, A. K.; Sridhar, P. R.; Kumaragurubaran, N.; Koh, Y.; Weber, I. T.; Mitsuya, H. Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of HIV protease inhibitors that combat drug resistance. ChemMedChem 2006, 1, 939950,  DOI: 10.1002/cmdc.200600103 .
        (c) Ghosh, A. K. Harnessing nature’s Insight: design of aspartyl protease inhibitors from treatment of drug-resistant HIV to Alzheimer’s disease. J. Med. Chem. 2009, 52, 21632176,  DOI: 10.1021/jm900064c
      161. 161
        Vermeir, M.; Lachau-Durand, S.; Mannens, G.; Cuyckens, F.; van Hoof, B.; Raoof, A. Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjects. Drug Metab. Dispos. 2009, 37, 809820,  DOI: 10.1124/dmd.108.024109
      162. 162
        Sadler, B. M.; Chittick, G. E.; Polk, R. E.; Slain, D.; Kerkering, T. M.; Studenberg, S. D.; Lou, Y.; Moore, K. H.; Woolley, J.; Stein, D. S. Metabolic disposition and pharmacokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjects. J. Clin. Pharmacol. 2001, 41, 386396,  DOI: 10.1177/00912700122010249
      163. 163
        (a) Ghosh, A. K.; Xu, C.; Rao, K. V.; Baldridge, A.; Agniswamy, J.; Wang, Y.; Weber, I. T.; Aoki, M.; Miguel, S.; Amano, M.; Mitsuya, H. Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors. ChemMedChem 2010, 5, 18501854,  DOI: 10.1002/cmdc.201000318 .
        (b) Zhang, H.; Wang, Y.; Shen, C.; Agniswamy, J.; Rao, K. V.; Xu, C.; Ghosh, A. K.; Harrison, R. W.; Weber, I. T. Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL0519) fills the S2 binding pocket of selected mutants of HIV-1 protease. J. Med. Chem. 2013, 56, 10741083,  DOI: 10.1021/jm301519z .
        (c) Ghosh, A. K.; Rao, K. V.; Nyalapatla, P. R.; Osswald, H. L.; Martyr, C. D.; Aoki, M.; Hayashi, H.; Agniswamy, J.; Wang, Y.; Bulut, H.; Das, D.; Weber, I. T.; Mitsuya, H. Design and development of highly potent HIV-1 protease inhibitors with a crown-like oxotricyclic core as the P2-ligand to combat multidrug-resistant HIV variants. J. Med. Chem. 2017, 60, 42674278,  DOI: 10.1021/acs.jmedchem.7b00172
      164. 164
        (a) Chang, Z. The discovery of Qinghaosu (artemisinin) as an effective anti-malaria drug: A unique China story. Sci. China: Life Sci. 2016, 59, 8188,  DOI: 10.1007/s11427-015-4988-z .
        (b) Cui, L.; Su, X. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev. Anti-Infect. Ther. 2009, 7, 9991013,  DOI: 10.1586/eri.09.68 .
        (c) Fernández-Álvaro, E.; Hong, W. D.; Nixon, G. L.; O’Neill, P. M.; Calderón, F. Antimalarial chemotherapy: natural product inspired development of preclinical and clinical candidates with diverse mechanisms of action. J. Med. Chem. 2016, 59, 55875603,  DOI: 10.1021/acs.jmedchem.5b01485 .
        (d) Wells, T. N.; Huijsduijnen, R. H.; Voorhis, W. C. Malaria medicines: a glass half full?. Nat. Rev. Drug Discovery 2015, 14, 424442,  DOI: 10.1038/nrd4573 .
        (e) Sharma, B.; Singh, P.; Singh, A. K.; Awasthi, S. K. Advancement of chimeric hybrid drugs to cure malaria infection: an overview with special emphasis on endoperoxide pharmacophores. Eur. J. Med. Chem. 2021, 219, 113408,  DOI: 10.1016/j.ejmech.2021.113408
      165. 165
        (a) Zeng, M.; Li, L.; Chen, S.; Li, C.; Liang, X.; Chen, M.; Clardy, J. Chemical transformations of qinghaosu, a peroxidic antimalarial. Tetrahedron 1983, 39, 29412946,  DOI: 10.1016/S0040-4020(01)92155-6 .
        (b) Lin, A. J.; Klayman, D. L.; Hoch, J. M.; Silverton, J. M.; George, C. F. Thermal rearrangement and decomposition products of artemisinin (qinghaosu). J. Org. Chem. 1985, 50, 45044508,  DOI: 10.1021/jo00223a017
      166. 166
        (a) Gomes, G.; Vil, V.; Terent’ev, A.; Alabugin, I. V. Stereoelectronic source of the anomalous stability of bis-peroxides. Chem. Sci. 2015, 6, 67836791,  DOI: 10.1039/C5SC02402A .
        (b) Edwards, J. O.; Pearson, R. G. The factors determining nucleophilic reactivities. J. Am. Chem. Soc. 1962, 84, 1624,  DOI: 10.1021/ja00860a005 .
        (c) Hoz, S.; Buncel, E. The α-effect: a critical examination of the phenomenon and its origin. Isr. J. Chem. 1985, 26, 313319,  DOI: 10.1002/ijch.198500113 .
        (d) Buncel, E.; Um, I. The α-effect and its modulation by solvent. Tetrahedron 2004, 60, 78017825,  DOI: 10.1016/j.tet.2004.05.006
      167. 167
        Haynes, R. K.; Krishna, S. Artemisinins: activities and actions. Microbes Infect. 2004, 6, 13391346,  DOI: 10.1016/j.micinf.2004.09.002
      168. 168
        (a) O’Neill, P. M.; Barton, V. E.; Ward, S. A. The molecular mechanism of action of artemisinin - the debate continues. Molecules 2010, 15, 17051721,  DOI: 10.3390/molecules15031705 .
        (b) Li, Z.; Li, Q.; Wu, J.; Wang, M.; Yu, J. Artemisinin and its derivatives as a repurposing anticancer agent: what else do we need to do?. Molecules 2016, 21, 1331,  DOI: 10.3390/molecules21101331 .
        (c) Cui, L.; Su, X. Z. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev. Anti-Infect. Ther. 2009, 7, 9991013,  DOI: 10.1586/eri.09.68 .
        (d) Wang, J.; Zhang, C. J.; Chia, W.; Loh, C.; Li, Z.; Lee, Y. M.; He, Y.; Yuan, L. X.; Lim, T. K.; Liu, M.; Liew, C. X.; Lee, Y. Q.; Zhang, J.; Lu, N.; Lim, C. T.; Hua, Z. C.; Liu, B.; Shen, H. M.; Tan, K. S.; Lin, Q. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat. Commun. 2015, 6, 10111,  DOI: 10.1038/ncomms10111
      169. 169
        (a) Lin, A. J.; Klayman, D. L.; Milhous, W. K. Antimalarial activity of new water-soluble dihydroartemisinin derivatives. J. Med. Chem. 1987, 30, 21472150,  DOI: 10.1021/jm00394a037 .
        (b) Lin, A. J.; Zikry, A. B.; Kyle, D. E. Antimalarial activity of new dihydroartemisinin derivatives. 7. 4-(p-Substituted phenyl)-4(R or S)-[10(δ. or β)-dihydroartemisininoxy]butyric acids. J. Med. Chem. 1997, 40, 13961400,  DOI: 10.1021/jm9607919
      170. 170
        Jung, M.; Lee, S. Stability of acetal and non acetal-type analogues of artemisinin in simulated stomach acid. Bioorg. Med. Chem. Lett. 1998, 8, 10031006,  DOI: 10.1016/S0960-894X(98)00160-7
      171. 171
        Jung, M.; Lee, K.; Kendrick, H.; Robinson, B. L.; Croft, S. L. Synthesis, stability, and antimalarial activity of new hydrolytically stable and water-soluble (+)-deoxoartelinic acid. J. Med. Chem. 2002, 45, 49404944,  DOI: 10.1021/jm020244p
      172. 172
        Singh, C.; Verma, V. P.; Hassam, M.; Singh, A. S.; Naikade, N. K.; Puri, S. K. New orally active amino- and hydroxy-functionalized 11-azaartemisinins and their derivatives with high order of antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice. J. Med. Chem. 2014, 57, 24892497,  DOI: 10.1021/jm401774f
      173. 173
        Haynes, R. K.; Fugmann, B.; Stetter, J.; Rieckmann, K.; Heilmann, H.; Chan, H.; Cheung, M.; Lam, W.; Wong, H.; Croft, S. L.; Vivas, L.; Rattray, L.; Stewart, L.; Peters, W.; Robinson, B. L.; Edstein, M. D.; Kotecka, B.; Kyle, D. E.; Beckermann, B.; Gerisch, M.; Radtke, M.; Schmuck, G.; Steinke, W.; Wollborn, U.; Schmeer, K.; Romer, A. Artemisone - a highly active antimalarial drug of the artemisinin class. Angew. Chem., Int. Ed. 2006, 45, 20822088,  DOI: 10.1002/anie.200503071
      174. 174
        Wang, X.; Dong, Y.; Wittlin, S.; Charman, S. A.; Chiu, F. C.; Chollet, J.; Katneni, K.; Mannila, J.; Morizzi, J.; Ryan, E.; Scheurer, C.; Steuten, J.; Tomas, J. S.; Snyder, C.; Vennerstrom, J. L. Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. J. Med. Chem. 2013, 56, 25472555,  DOI: 10.1021/jm400004u
      175. 175
        (a) Benoit-Vical, F.; Lelievre, J.; Berry, A.; Deymier, C.; Dechy-Cabaret, O.; Cazelles, J.; Loup, C.; Robert, A.; Magnaval, J.; Meunier, B. Trioxaquines are new antimalarial agents active on all erythrocytic forms, including gametocytes. Antimicrob. Agents Chemother. 2007, 51, 14631472,  DOI: 10.1128/AAC.00967-06 .
        (b) Cosledan, F.; Fraisse, L.; Pellet, A.; Guillou, F.; Mordmuller, B.; Kremsner, P. G.; Moreno, A.; Mazier, D.; Maffrand, J.-P.; Meunier, B. Selection of a trioxaquine as an antimalarial drug candidate. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 1757917584,  DOI: 10.1073/pnas.0804338105 .
        (c) Waseem, Y.; Hasan, C. A.; Ahmed, F. Artemisinin: A promising adjunct for cancer therapy. Cureus. 2018, 10 (11), e3628  DOI: 10.7759/cureus.3628 .
        (d) Fröhlich, T.; Çapcı, K. A.; Reiter, C.; Tsogoeva, S. B. Artemisinin-derived dimers: potent antimalarial and anticancer agents. J. Med. Chem. 2016, 59 (16), 736088,  DOI: 10.1021/acs.jmedchem.5b01380 .
        (e) Singh, N. P.; Lai, H. C.; Park, J. S.; Gerhardt, T. E.; Kim, B. J.; Wang, S.; Sasaki, T. Effects of artemisinin dimers on rat breast cancer cells in vitro and in vivo. Anticancer Res. 2011, 31 (12), 41114.
        (f) Moses, B. S.; McCullough, S.; Fox, J. M.; Mott, B. T.; Bentzen, S. M.; Kim, M.; Tyner, J. W.; Lapidus, R. G.; Emadi, A.; Rudek, M. A.; Kingsbury, T. J.; Civin, C. Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclax. Blood Adv. 2021, 5 (3), 711724,  DOI: 10.1182/bloodadvances.2020003429 .
        (g) Cheng, C.; Wang, T.; Song, Z.; Peng, L.; Gao, M.; Hermine, O.; Rousseaux, S.; Khochbin, S.; Mi, J. Q.; Wang, J. Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044. Cancer Med. 2018, 7 (2), 380396,  DOI: 10.1002/cam4.1276
      176. 176
        (a) Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.; Chiu, F. C.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam, M.; Tomas, J. S.; Scheurer, C.; Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N. Identification of an antimalarial synthetic trioxolane drugdevelopment candidate. Nature 2004, 430, 900904,  DOI: 10.1038/nature02779 .
        (b) Dong, Y.; Tang, Y.; Chollet, J.; Matile, H.; Wittlin, S.; Charman, S. A.; Charman, W. N.; Tomas, J. S.; Scheurer, C.; Snyder, C. Effect of functional group polarity on the antimalarial activity of spiro and dispiro-1,2,4-trioxolanes. Bioorg. Med. Chem. 2006, 14, 63686382,  DOI: 10.1016/j.bmc.2006.05.041 .
        (c) Kim, H. S.; Hammill, J. T.; Guy, R. K. Seeking the elusive long-acting ozonide: discovery of artefenomel (OZ439). J. Med. Chem. 2017, 60, 26512653,  DOI: 10.1021/acs.jmedchem.7b00299 .
        (d) Dong, Y.; Wang, X.; Kamaraj, S.; Bulbule, V. J.; Chiu, F. C.; Chollet, J.; Dhanasekaran, M.; Hein, C. D.; Papastogiannidis, P.; Morizzi, J.; Shackleford, D. M.; Barker, H.; Ryan, E.; Scheurer, C.; Tang, Y.; Zhao, Q.; Zhou, L.; White, K. L.; Urwyler, H.; Charman, W. N.; Matile, H.; Wittlin, S.; Charman, S. A.; Vennerstrom, J. L. Structure-activity relationship of the antimalarial ozonide artefenomel (OZ439). J. Med. Chem. 2017, 60, 26542668,  DOI: 10.1021/acs.jmedchem.6b01586 .
        (e) Phyo, A. P.; Jittamala, P.; Nosten, F. N.; Pukrittayakamee, S.; Imwong, M.; White, N. J.; Duparc, S.; Macintyre, F.; Baker, M.; Möhrle, J. J. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect. Dis. 2016, 16, 6169,  DOI: 10.1016/S1473-3099(15)00320-5
      177. 177
        Opsenica, I.; Opsenica, D.; Smith, K. S.; Milhous, W. K.; Solaja, B. A. Chemical stability of the peroxide bond enables diversified synthesis of potent tetraoxane antimalarials. J. Med. Chem. 2008, 51, 22612266,  DOI: 10.1021/jm701417a
      178. 178
        (a) Ellis, G. L.; Amewu, R.; Sabbani, S.; Stocks, P. A.; Shone, A.; Stanford, D.; Gibbons, P.; Davies, J.; Vivas, L.; Charnaud, S.; Bongard, E.; Hall, C.; Rimmer, K.; Lozanom, S.; Jesús, M.; Gargallo, D.; Ward, S. A.; O’Neill, P. M. Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles. J. Med. Chem. 2008, 51, 21702177,  DOI: 10.1021/jm701435h .
        (b) O’Neill, P. M.; Amewu, R. K.; Nixon, G. L.; El Garah, F. B.; Mungthin, M.; Chadwick, J.; Shone, A. E.; Vivas, L.; Lander, H.; Barton, V.; Muangnoicharoen, S.; Bray, P. G.; Davies, J.; Park, B. K.; Wittlin, S.; Brun, R.; Preschel, M.; Zhang, K.; Ward, S. A. Identification of a 1,2,4,5-tetraoxane antimalarial drug-development candidate (RKA182) with superior properties to the semisynthetic artemisinins. Angew. Chem., Int. Ed. 2010, 49, 56935697,  DOI: 10.1002/anie.201001026 .
        (c) Marti, F.; Chadwick, J.; Amewu, R. K.; Burrell-Saward, H.; Srivastava, A.; Ward, S. A.; Sharma, R.; Berry, N.; O’Neill, P. M. Second generation analogues of RKA182: synthetic tetraoxanes with outstanding in vitro and in vivo antimalarial activities. MedChemComm 2011, 2, 661665,  DOI: 10.1039/c1md00102g .
        (d) O’Neill, P. M.; Amewu, R. K.; Charman, S. A.; Sabbani, S.; Gnadig, N. F.; Straimer, J.; Fidock, D. A.; Shore, E. R.; Roberts, N. L.; Wong, M. H.; Hong, W. D.; Pidathala, C.; Riley, C.; Murphy, B.; Aljayyoussi, G.; Gamo, F. J.; Sanz, L.; Rodrigues, J.; Cortes, C. C.; Herreros, E.; Angulo-Barturen, I.; Jimenez-Dıaz, M. B.; Bazaga, S. F.; Martınez-Martınez, M. S.; Campo, B.; Sharma, R.; Ryan, E.; Shackleford, D. M.; Campbell, S.; Smith, D. A.; Wirjanata, G.; Noviyanti, R.; Price, R. N.; Marfurt, J.; Palmer, M. J.; Copple, I. M.; Mercer, A. E.; Ruecker, A.; Delves, M. J.; Sinden, R. E.; Sieg, P.; Davies, J.; Rochford, R.; Kocken, C. H.; Zeeman, A.; Nixon, G. L.; Biagini, G. A.; Ward, S. A. A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance. Nat. Commun. 2017, 8, 15159,  DOI: 10.1038/ncomms15159
      179. 179
        (a) Counter, F. T.; Ensminger, P. W.; Preston, D. A.; Wu, C. Y.; Greene, J. M.; Felty-Duckworth, A. M.; Paschal, J. W.; Kirst, H. A. Synthesis and antimicrobial evaluation of dirithromycin (AS-E 13. LY237216), a new macrolide antibiotic derived from erythromycin. Antimicrob. Agents Chemother. 1991, 35, 11161126,  DOI: 10.1128/AAC.35.6.1116 .
        (b) Mazzei, T.; Surrenti, C.; Novelli, A.; Biagini, M. R.; Fallani, S.; Cassetta, M. I.; Conti, S.; Surrenti, E. Pharmacokinetics of dirithromycin in patients with mild or moderate cirrhosis. Antimicrob. Agents Chemother. 1999, 43, 15561559,  DOI: 10.1128/AAC.43.7.1556 .
        (c) Sides, G. D.; Cerimele, B. J.; Black, H. R.; Bosch, U.; DeSante, K. A. Pharmacokinetics of dirithromycin. J. Antimicrob. Chemother. 1993, 31, 6575,  DOI: 10.1093/jac/31.suppl_C.65 .
        (d) Shinkai, I.; Ohta, Y. Dirithromycin. Bioorg. Med. Chem. 1996, 4, 521522,  DOI: 10.1016/0968-0896(96)00052-1
      180. 180
        (a) Khabibullina, N. F.; Tereshchenkov, A. G.; Komarova, E. S.; Syroegin, E. A.; Shiriaev, D. I.; Paleskava, A.; Kartsev, V. G.; Bogdanov, A. A.; Konevega, A. L.; Dontsova, O. A.; Sergiev, P. V.; Osterman, I. A.; Polikanov, Y. S. Structure of dirithromycin bound to the bacterial ribosome suggests new ways for rational improvement of macrolides. Antimicrob. Agents Chemother. 2019, 63, e02266  DOI: 10.1128/AAC.02266-18 .
        (b) Pichkur, E. B.; Paleskava, A.; Tereshchenkov, A. G.; Kasatsky, P.; Komarova, E. S.; Shiriaev, D. I.; Bogdanov, A. A.; Dontsova, O. A.; Osterman, I. A.; Sergiev, P. V.; Polikanov, Y. S.; Myasnikov, A. G.; Konevega, A. L. Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the E. coli 70S ribosome. RNA 2020, 26, 715723,  DOI: 10.1261/rna.073817.119
      181. 181
        (a) Wöhr, T.; Wahl, F.; Nefzi, A.; Rohwedder, B.; Sato, T.; Sun, X.; Mutter, M. Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesis. J. Am. Chem. Soc. 1996, 118, 92189227,  DOI: 10.1021/ja961509q .
        (b) Chaume, G.; Barbeau, O.; Lesot, P.; Brigaud, T. Synthesis of 2-trifluoromethyl-1,3-oxazolidines as hydrolytically stable pseudoprolines. J. Org. Chem. 2010, 75, 41354145,  DOI: 10.1021/jo100518t .
        (c) Malquin, N.; Rahgoshay, K.; Lensen, N.; Chaume, G.; Miclet, E.; Brigaud, T. CF2H as a hydrogen bond donor group for the fine tuning of peptide bond geometry with difluoromethylated pseudoprolines. Chem. Commun. 2019, 55, 1248712490,  DOI: 10.1039/C9CC05771D .
        (d) Chaume, G.; Simon, J.; Caupéne, C.; Lensen, N.; Miclet, E.; Brigaud, T. Incorporation of CF3-pseudoprolines into peptides: a methodological study. J. Org. Chem. 2013, 78, 1014410153,  DOI: 10.1021/jo401494q
      182. 182
        (a) Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. M.; Graham, D. J.; Hu, B.; Huang, Q.; Kargman, S.; Kozlowski, J.; Liu, R.; McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.; Wang, D.; Wu, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W. Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem 2013, 8, 19301940,  DOI: 10.1002/cmdc.201300343 .
        (b) Yu, W.; Tong, L.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Coburn, C. A.; Selyutin, O.; Chen, L.; Rokosz, L.; Agrawal, S.; Liu, R.; Curry, S.; McMonagle, P.; Ingravallo, P.; Asante-Appiah, E.; Chen, S.; Kozlowski, J. A. Discovery of chromane containing hepatitis C virus (HCV) NS5A inhibitors with improved potency against resistance-associated variants. J. Med. Chem. 2016, 59, 1022810243,  DOI: 10.1021/acs.jmedchem.6b01234 .
        (c) Tong, L.; Yu, W.; Chen, L.; Selyutin, O.; Dwyer, M. P.; Nair, A. G.; Mazzola, R.; Kim, J.; Sha, D.; Yin, J.; Ruck, R. T.; Davies, R. W.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Liu, R.; Agrawal, S.; Xia, E.; Curry, S.; McMonagle, P.; Bystol, K.; Lahser, F.; Carr, D.; Rokosz, L.; Ingravallo, P.; Chen, S.; Feng, K.; Cartwright, M.; Asante-Appiah, E.; Kozlowski, J. A. Discovery of ruzasvir (MK-8408): a potent, pan-genotype HCV NS5A inhibitor with optimized activity against common resistance-associated polymorphisms. J. Med. Chem. 2017, 60, 290306,  DOI: 10.1021/acs.jmedchem.6b01310 .
        (d) Yu, W.; Tong, L.; Selyutin, O.; Chen, L.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Yin, J.; Ruck, R. T.; Curry, S.; McMonagle, P.; Agrawal, S.; Rokosz, L.; Carr, D.; Ingravallo, P.; Bystol, K.; Lahser, F.; Liu, R.; Chen, S.; Feng, K.; Cartwright, M.; Asante-Appiah, E.; Kozlowski, J. A. Discovery of MK-6169, a potent pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. J. Med. Chem. 2018, 61, 39844003,  DOI: 10.1021/acs.jmedchem.7b01927 .
        (e) https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208261Orig1s000PharmR.pdf (accessed April 2, 2021.)
      183. 183
        (a) Reading, C.; Cole, M. Clavulanic acid: a β-lactamase-inhibiting β-lactam from Streptomyces clavuligerus. Antimicrob. Agents Chemother. 1977, 11, 852857,  DOI: 10.1128/AAC.11.5.852 .
        (b) Buynak, J. D. Understanding the longevity of the β-lactam antibiotics and of antibiotic/β-lactamase inhibitor combinations. Biochem. Pharmacol. 2006, 71, 930940,  DOI: 10.1016/j.bcp.2005.11.012
      184. 184
        (a) Brown, R. P.; Aplin, R. T.; Schofield, C. J. Inhibition of TEM-2 β-lactamase from Escherichia coli by clavulanic acid: observation of intermediates by electrospray ionization mass spectrometry. Biochemistry 1996, 35, 1242112432,  DOI: 10.1021/bi961044g .
        (b) Imtiaz, U.; Billings, E.; Knox, J. R.; Manavathu, E. K.; Lerner, S. A.; Mobashery, S. Inactivation of class A β-lactamases by clavulanic acid: the role of arginine-244 in a proposed nonconcerted sequence of events. J. Am. Chem. Soc. 1993, 115, 44354442,  DOI: 10.1021/ja00064a003
      185. 185
        Haginaka, J.; Nakagawa, T.; Uno, T. Stability of clavulanic acid in aqueous solutions. Chem. Pharm. Bull. 1981, 29, 33343341,  DOI: 10.1248/cpb.29.3334
      186. 186
        (a) Adam, D.; de Visser, I.; Koeppe, P. Pharmacokinetics of amoxicillin and clavulanic acid administered alone and in combination. Antimicrob. Agents Chemother. 1982, 22, 353357,  DOI: 10.1128/AAC.22.3.353 .
        (b) Navarro, A. S. New formulations of amoxicillin/clavulanic acid. Clin. Pharmacokinet. 2005, 44, 10971115,  DOI: 10.2165/00003088-200544110-00001 .
        (c) De Velde, F.; De Winter, B. C. M.; Koch, B. C. P.; Van Gelder, T.; Mouton, J. W. and the COMBACTE-NET consortium. Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis. J. Antimicrob. Chemother. 2018, 73, 469476,  DOI: 10.1093/jac/dkx376
      187. 187
        (a) Krishnan, B. R.; James, K. D.; Polowy, K.; Bryant, B.; Vaidya, A.; Smith, S.; Laudeman, C. P. CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. J. Antibiot. 2017, 70, 130135,  DOI: 10.1038/ja.2016.89 .
        (b) Sofjan, A. K.; Mitchell, A.; Shah, D. N.; Nguyen, T.; Sim, M.; Trojcak, A.; Beyda, N. D.; Garey, K. W. Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy. J. Global Antimicrob. Resist. 2018, 14, 5864,  DOI: 10.1016/j.jgar.2018.02.013
      188. 188
        Kofla, G.; Ruhnke, M. Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis: review of the literature. Eur. J. Med.Res. 2011, 16, 159166,  DOI: 10.1186/2047-783X-16-4-159
      189. 189
        (a) Johns, B. A.; Kawasuji, T.; Weatherhead, J. G.; Taishi, T.; Temelkoff, D. P.; Yoshida, H.; Akiyama, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Jeffrey, J.; Foster, S. A.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Johnson, M. N.; Garvey, E. P.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744). J. Med. Chem. 2013, 56, 59015916,  DOI: 10.1021/jm400645w .
        (b) Kawasuji, T.; Johns, B. A.; Yoshida, H.; Weatherhead, J. G.; Akiyama, T.; Taishi, T.; Taoda, Y.; Mikamiyama-Iwata, M.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Garvey, E. P.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles. J. Med. Chem. 2013, 56, 11241135,  DOI: 10.1021/jm301550c .
        (c) Kawasuji, T.; Johns, B. A.; Yoshida, H.; Taishi, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors. 1. Molecular design and establishment of an advanced two-metal binding pharmacophore. J. Med. Chem. 2012, 55, 87358744,  DOI: 10.1021/jm3010459
      190. 190
        (a) Tsiang, M.; Jones, G. S.; Goldsmith, J.; Mulato, A.; Hansen, D.; Kan, E.; Tsai, L.; Bam, R. A.; Stepan, G.; Stray, K. M.; Niedziela-Majka, A.; Yant, S. R.; Yu, H.; Kukolj, G.; Cihlar, T.; Lazerwith, S. E.; White, K. L.; Jin, H. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob. Agents Chemother. 2016, 60, 70867097,  DOI: 10.1128/AAC.01474-16 .
        (b) Lazerwith, S. E.; Cai, R.; Chen, X.; Chin, G.; Desai, M. C.; Eng, S.; Jacques, R.; Ji, M.; Jones, G.; Martin, H.; McMahon, C.; Mish, M.; Morganelli, P.; Mwangi, J.; Pyun, H.; Schmitz, U.; Stepan, G.; Szwarcberg, J.; Tang, J.; Tsiang, M.; Wang, J.; Wang, K.; White, K.; Wiser, L.; Zack, J.; Jin, H. Discovery of bictegravir (GS-9883), a novel, unboosted, once-daily HIV-1 integrase strand transfer inhibitor (INSTI) with improved pharmacokinetics and in vitro resistance profile. ASM Microbe: Boston, MA, 2016.
      191. 191
        Deeks, E. D. Bictegravir/emtricitabine/tenofovir alafenamide: a review in HIV-1 infection. Drugs 2018, 78, 18171828,  DOI: 10.1007/s40265-018-1010-7
      192. 192
        (a) Wu, Y.-J.; Guernon, J.; Rajamani, R.; Toyn, J. H.; Ahlijanian, M. K.; Albright, C. F.; Muckelbauer, J.; Chang, C.; Camac, D.; Macor, J. E.; Thompson, L. A. Discovery of furo[2,3-d][1,3]thiazinamines as β-amyloid cleaving enzyme-1 (BACE1) inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 57295731,  DOI: 10.1016/j.bmcl.2016.10.055 .
        (b) Wu, Y.-J.; Guernon, J.; Park, H.; Thompson, L. A. Expedient synthesis of fluoro[2,3-d[1,3]thiazinamines and pyrano-[2,3-d][1,3]thiazinamines from enones and thiourea. J. Org. Chem. 2016, 81, 33863390,  DOI: 10.1021/acs.joc.5b02705
      193. 193
        Futamura, A.; Suzuki, R.; Tamura, Y.; Kawamoto, H.; Ohmichi, M.; Hino, N.; Tokumaru, Y.; Kirinuki, S.; Hiyoshi, T.; Aoki, T.; Kambe, D.; Nozawa, D. Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia. Bioorg. Med. Chem. 2020, 28, 115489,  DOI: 10.1016/j.bmc.2020.115489
      194. 194
        (a) Miller, T. W.; Goegelman, R. T.; Weston, R. G.; Putter, I.; Wolf, F. J. Cephamycins, a new family of β-lactam antibiotics. II. Isolation and chemical characterization. Antimicrob. Agents Chemother. 1972, 2, 132135,  DOI: 10.1128/AAC.2.3.132 .
        (b) Stapley, E. O.; Birnbaum, J.; Miller, A. K.; Wallick, H.; Hendlin, D.; Woodruff, H. B. Cefoxitin and cephamycins: microbiological studies. Clin. Infect. Dis. 1979, 1, 7387,  DOI: 10.1093/clinids/1.1.73
      195. 195
        Brites, L. M.; Oliveira, L. M.; Barboza, M. Kinetic study on cephamycin C degradation. Appl. Biochem. Appl. Biochem. Biotechnol. 2013, 171, 21212128,  DOI: 10.1007/s12010-013-0502-x
      196. 196
        (a) Hagmann, W. K.; Thompson, K. R.; Shah, S. K.; Finke, P. E.; Ashe, B. M.; Weston, H.; Maycock, A. L.; Doherty, J. B. The effect of N-acyl substituents on the stability of monocyclic β-lactam inhibitors of human leukocyte elastase. Bioorg. Med. Chem. Lett. 1992, 2, 681684,  DOI: 10.1016/S0960-894X(00)80390-X .
        (b) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L. Orally active β-lactam inhibitors of human leukocyte elastase. 3. Stereospecific synthesis and structure-activity relationships for 3,3-dialkylazetidin-2-ones. J. Med. Chem. 1995, 38, 24492462,  DOI: 10.1021/jm00013a021 .
        (c) Doherty, J. B.; Shah, S. K.; Finke, P. E.; Dorn, C. P.; Hagmann, W. K.; Hale, J. J.; Kissinger, A. L.; Thompson, K. R.; Brause, K.; Chandler, G. O. Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: a potent, orally active monocyclic β-lactam inhibitor of human polymorphonuclear leukocyte elastase. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 87278731,  DOI: 10.1073/pnas.90.18.8727 .
        (d) Vincent, S. H.; Painter, S. K.; Luffer-Atlas, D.; Karanam, B. V.; McGowan, E.; Cioffe, C.; Doss, G.; Chiu, S. Orally active inhibitors of human leukocyte elastase. II. Disposition of L-694,458 in rats and rhesus monkeys. Drug Metab. Dispos. 1997, 25, 932939
      197. 197
        Halas, C. J. Eszopiclone. Am. J. Health-Syst. Pharm. 2006, 63, 4148,  DOI: 10.2146/ajhp050357
      198. 198
        (a) Shelton, J.; Lu, X.; Hollenbaugh, J. A.; Cho, J. H.; Amblard, F.; Schinazi, R. F. Metabolism, biochemical actions, and chemical synthesis of anticancer nucleosides, nucleotides, and base analogues. Chem. Rev. 2016, 116, 1437914455,  DOI: 10.1021/acs.chemrev.6b00209 .
        (b) Seley-Radtke, K.; Yates, M. K. The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part I: Early structural modifications to the nucleoside scaffold. Antiviral Res. 2018, 154, 6686,  DOI: 10.1016/j.antiviral.2018.04.004 .
        (c) Seley-Radtke, K.; Yates, M. K. The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold. Antiviral Res. 2019, 162, 521,  DOI: 10.1016/j.antiviral.2018.11.016 .
        (d) Li, G.; Yue, T.; Zhang, P.; Gu, W.; Gao, L.-J.; Tan, L. Drug discovery of nucleos(t)ide antiviral agents: dedicated to Prof. Dr. Erik De Clercq on occasion of his 80th birthday. Molecules 2021, 26, 923,  DOI: 10.3390/molecules26040923 .
        (e) Guinan, M.; Benckendorff, C.; Smith, M.; Miller, G. J. Recent advances in the chemical synthesis and evaluation of anticancer nucleoside analogues. Molecules 2020, 25, 2050,  DOI: 10.3390/molecules25092050
      199. 199
        (a) Garrett, E. R.; Seydel, J. K.; Sharpen, A. J. The acid-catalyzed solvolysis of pyrimidine nucleosides. J. Org. Chem. 1966, 31, 22192227,  DOI: 10.1021/jo01345a033 .
        (b) Zoltewicz, J. A.; Clark, D. F.; Sharpless, T. W.; Grahe, G. Kinetics and mechanism of the acid-catalyzed hydrolysis of some purine nucleosides. J. Am. Chem. Soc. 1970, 92, 17411750,  DOI: 10.1021/ja00709a055 .
        (c) Garrett, E. R.; Mehta, P. Solvolysis of adenine nucleosides. I. Effects of sugars and adenine substituents on acid solvolyses. J. Am. Chem. Soc. 1972, 94, 85328541,  DOI: 10.1021/ja00779a040 .
        (d) York, J. L. Effect of the structure of the glycon on the acid-catalyzed hydrolysis of adenine nucleosides. J. Org. Chem. 1981, 46, 21712173,  DOI: 10.1021/jo00323a040 .
        (e) Gates, K. S. An overview of chemical processes that damage cellular DNA: spontaneous hydrolysis, alkylation, and reactions with radicals. Chem. Res. Toxicol. 2009, 22, 17471760,  DOI: 10.1021/tx900242k
      200. 200
        Pogocki, D.; Schöneich, C. Chemical stability of nucleic acid-derived drugs. J. Pharm. Sci. 2000, 89, 443456,  DOI: 10.1002/(SICI)1520-6017(200004)89:4<443::AID-JPS2>3.3.CO;2-N
      201. 201
        (a) Minami, T.; Nakagawa, H.; Nabeshima, M.; Kadota, E.; Namikawa, K.; Kawaki, H.; Okazaki, Y. Nephrotoxicity induced by adenine and its analogues: relationship between structure and renal injury. Biol. Pharm. Bull. 1994, 17, 10321037,  DOI: 10.1248/bpb.17.1032 .
        (b) Philips, F. S.; Thiersch, J. B.; Bendich, A.; Borgatta, M. Adenine intoxication in relation to in vivo formation and deposition of 2,8-dioxyadenine in renal tubules. J. Pharmacol. Exp. Ther. 1952, 104, 2030
      202. 202
        (a) Frank, K. B.; Connell, E. V.; Holman, M. J.; Huryn, D. M.; Sluboski, B. C.; Tam, S. Y.; Todaro, L. J.; Weigele, M.; Richman, D. D.; Mitsuya, H.; Broder, S.; Sim, I. S. Anabolism and mechanism of action of Ro24–5098, an isomer of 2′,3′-dideoxyadenosine (ddA) with anti-HIV activity. Ann. N. Y. Acad. Sci. 1990, 616, 408414,  DOI: 10.1111/j.1749-6632.1990.tb17860.x .
        (b) Andrade, C. H.; de Freitas, L. M.; de Oliveira, V. Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism. Braz. J. Pharm. Sci. 2011, 47, 209230,  DOI: 10.1590/S1984-82502011000200003 .
        (c) Martin, J. C.; Hitchcock, M. J. M.; De Clercq, E.; Prusoff, W. H. Early nucleoside reverse transcriptase inhibitors for the treatment of HIV: A brief history of stavudine (D4T) and its comparison with other dideoxynucleosides. Antiviral Res. 2010, 85, 3438,  DOI: 10.1016/j.antiviral.2009.10.006
      203. 203
        Hirt, D.; Bardin, C.; Diagbouga, S.; Nacro, B.; Hien, H.; Zoure, E.; Rouet, F.; Ouiminga, A.; Urien, S.; Foulongne, V.; Van De Perre, P.; Treuyer, J.; Msellati, P. Didanosine population pharmacokinetics in west african human immunodeficiency virus-infected children administered once-daily tablets in relation to efficacy after one year of treatment. Antimicrob. Agents Chemother. 2009, 53, 43994406,  DOI: 10.1128/AAC.01187-08
      204. 204
        (a) Kelley, J. A.; Litterst, C. L.; Roth, J. S.; Vistica, D. T.; Poplack, D. G.; Cooney, D. A.; Nadkarni, M.; Balis, F. M.; Broder, S.; Johns, D. G. The disposition and metabolism of 2′,3′-dideoxycytidine, an in vitro inhibitor of human T-lymphotrophic virus type III infectivity, in mice and monkeys. Drug Metab. Dispos. 1987, 15, 595601.
        (b) Klecker, R. W., Jr.; Collins, J. M.; Yarchoan, R. C.; Thomas, R.; McAtee, N.; Broder, S.; Myers, C. E. Pharmacokinetics of 2′,3′-dideoxycytidine in patients with AIDS and related disorders. J. Clin. Pharmacol. 1988, 28, 837842,  DOI: 10.1002/j.1552-4604.1988.tb03225.x
      205. 205
        (a) Marquez, V. E.; Tseng, C. K.; Mitsuya, H.; Aoki, C.; Kelley, J. A.; Ford, H.; Roth, J. S.; Broder, S.; Johns, D. G.; Driscoll, J. S. Acid-stable 2′-fluoro purine dideoxynucleosides as active agents against HIV. J. Med. Chem. 1990, 33, 978985,  DOI: 10.1021/jm00165a015 .
        (b) Marquez, V. E.; Tseng, C. K.-H.; Kelley, J. A.; Mitsuya, H.; Broder, S.; Roth, J. S.; Driscoll, J. S. 2′,3′-Dideoxy-2′-fluoro-ara-A. An acid-stable purine nucleoside active against human immunodeficiency virus (HIV). Biochem. Pharmacol. 1987, 36, 27192722,  DOI: 10.1016/0006-2952(87)90254-1 .
        (c) Russell, J. W.; Klunk, L. J. Comparative pharmacokinetics of new anti-HIV agents: 2′, 3′-dideoxyadenosine and 2′, 3′-dideoxyinosine. Biochem. Pharmacol. 1989, 38, 13851388,  DOI: 10.1016/0006-2952(89)90176-7
      206. 206
        (a) Liu, P.; Sharon, A.; Chu, C. K. Fluorinated nucleosides: synthesis and biological implication. J. Fluorine Chem. 2008, 129, 743766,  DOI: 10.1016/j.jfluchem.2008.06.007 .
        (b) Wójtowicz-Rajchel, H. Synthesis and applications of fluorinated nucleoside analogues. J. Fluorine Chem. 2012, 143, 1148,  DOI: 10.1016/j.jfluchem.2012.06.026
      207. 207
        Rozen, S.; Vints, I.; Lerner, A.; Hod, O.; Brothers, E. N.; Moncho, S. The chemistry of short-lived α-fluorocarbocations. J. Org. Chem. 2021, 86, 38823889,  DOI: 10.1021/acs.joc.0c02731
      208. 208
        Johnson, S. A. Nucleoside analogues in the treatment of haematological malignancies. Expert Opin. Pharmacother. 2001, 2, 929943,  DOI: 10.1517/14656566.2.6.929
      209. 209
        Avramis, V. I.; Plunkett, W. 2-Fluoro-ATP: a toxic metabolite of 9-β-d-arabinoxyl-2-fluroadenine. Biochem. Biophys. Res. Commun. 1983, 113, 3543,  DOI: 10.1016/0006-291X(83)90428-X
      210. 210
        (a) Carson, D. A.; Wasson, D. B.; Esparza, L. M.; Carrera, C. J.; Kipps, T. J.; Cottam, H. B. Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine. Proc. Natl. Acad. Sci. U. S. A. 1992, 89, 29702974,  DOI: 10.1073/pnas.89.7.2970 .
        (b) Lindemalm, S.; Liliemark, J.; Juliusson, J.; Larsson, R.; Albertioni, F. Cytotoxicity and pharmacokinetics of cladribine metabolite, 2-chloroadenine, in patients with leukemia. Cancer Lett. 2004, 210, 171177,  DOI: 10.1016/j.canlet.2004.03.007
      211. 211
        (a) Chilman-Blair, K.; Mealy, N. E.; Castaner, J. Clofarabine: treatment of acute leukemia. Drugs Future 2004, 29, 112120,  DOI: 10.1358/dof.2004.029.02.776206 .
        (b) Bonate, P.; Arthaud, L.; Cantrell, W.; Stephenson, K.; Secrist, J. A.; Weitman, S. Discovery and development of clofarabine: a nucleoside analogue for treating cancer. Nat. Rev. Drug Discovery 2006, 5, 855863,  DOI: 10.1038/nrd2055 .
        (c) Montgomery, J. A.; Shortnacy-Fowler, A. T.; Clayton, S. D.; Riordan, J. M.; Secrist, J. A. Synthesis and biologic activity of 2′-fluoro-2-halo derivatives of 9-β-d-arabinofuranosyladenine. J. Med. Chem. 1992, 35, 397401,  DOI: 10.1021/jm00080a029 .
        (d) Xie, C.; Plunke, W. Metabolism and actions of 2-chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine in human lymphoblastoid cells. Cancer Res. 1995, 55, 28472852.
        (e) Faderl, S.; Garcia-Manero, G.; Estrov, Z.; Ravandi, F.; Borthakur, G.; Cortes, J. E.; O’Brien, S.; Gandhi, V.; Plunkett, W.; Byrd, A.; Kwari, M.; Kantarjian, H. M. Oral clofarabine in the treatment of patients with higher-risk myelodysplastic syndrome. J. Clin. Oncol. 2010, 28, 27552760,  DOI: 10.1200/JCO.2009.26.3509 .
        (f) Hermann, R.; Karlsson, M. O.; Novakovic, A. M.; Terranova, N.; Fluck, M.; Munafo, A. The clinical pharmacology of cladribine tablets for the treatment of relapsing multiple sclerosis. Clin. Pharmacokinet. 2019, 58, 283297,  DOI: 10.1007/s40262-018-0695-9
      212. 212
        (a) Bolwell, B. J.; Cassileth, P. A.; Gale, R. P. High dose cytarabine: a review. Leukemia 1988, 2, 253260.
        (b) Capizzi, R. L.; White, J. C.; Powell, B. L.; Perrino, F. Effect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabine. Semin. Hematol. 1991, 28, 5469
      213. 213
        (a) Bergmann, W.; Feeney, R. J. Contributions to the study of marine products. The nucleosides of sponges. J. Org. Chem. 1951, 16, 981987,  DOI: 10.1021/jo01146a023 .
        (b) Bergmann, W.; Burke, D. C. Contributions to the study of marine products. The nucleosides of sponges. III. Spongothymidine and spongouridine. J. Org. Chem. 1955, 20, 15011507,  DOI: 10.1021/jo01128a007 .
        (c) Khalifa, S. A. M.; Elias, N.; Farag, M. A.; Chen, L.; Saeed, A.; Hegazy, M.-E. F.; Moustafa, M. S.; Abd El-Wahed, A.; Al-Mousawi, S. M.; Musharraf, S. G.; Chang, F.-R.; Iwasaki, A.; Suenaga, K.; Alajlani, M.; Goransson, U.; El-Seedi, H. R. Marine natural products: a source of novel anticancer drugs. Mar. Drugs 2019, 17, 491,  DOI: 10.3390/md17090491 .
        (d) Dyshlovoy, S. A.; Honecker, F. Marine compounds and cancer: the first two decades of XXI century. Mar. Drugs 2020, 18, 20,  DOI: 10.3390/md18010020
      214. 214
        (a) Sun, Y.; Sun, J.; Shi, S.; Jing, Y.; Yin, S.; Chen, Y.; Li, G.; Xu, Y.; He, Z. Synthesis, transport and pharmacokinetics of 5′-amino acid ester prodrugs of 1-β-d-arabinofuranosylcytosine. Mol. Pharmaceutics 2009, 6, 315325,  DOI: 10.1021/mp800200a .
        (b) Hamada, A.; Kawaguchi, T.; Nakano, M. Clinical pharmacokinetics of cytarabine formulations. Clin. Pharmacokinet. 2002, 41, 705718,  DOI: 10.2165/00003088-200241100-00002
      215. 215
        Zuckerman, T.; Ram, R.; Akria, L.; Koren-Michowitz, M.; Hoffman, R.; Henig, I.; Lavi, N.; Ofran, Y.; Horowitz, N. A.; Nudelman, O.; Tavor, S.; Yeganeh, S.; Gengrinovitch, S.; Flaishon, L.; Tessler, S.; Ben Yakar, R.; Rowe, J. M. BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a study. Blood Adv. 2019, 3, 37403749,  DOI: 10.1182/bloodadvances.2019000468
      216. 216
        Wright, J. A..; Wilson, D. P..; Fox, J. J. Fluoro sugar analogues of arabinosyl- and xylosylcytosines. J. Med. Chem. 1970, 13, 269272,  DOI: 10.1021/jm00296a024
      217. 217
        Pankiewicz, K. W. Fluorinated nucleosides. Carbohydr. Res. 2000, 327, 87105,  DOI: 10.1016/S0008-6215(00)00089-6
      218. 218
        (a) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. Synthesis of 2-deoxy-2,2-difluoro-d-ribose and 2-deoxy-2,2′-difluoro-d-ribofuranosyl nucleosides. J. Org. Chem. 1988, 53, 24062409,  DOI: 10.1021/jo00246a002 .
        (b) Hertel, L. W.; Kroin, J. S.; Grossman, C. S.; Grindey, G. B.; Dorr, A. F.; Storiolo, A. M. V.; Plunkett, W.; Gandhi, V.; Huang, P. Synthesis and biological activity of 2′,2′-difluorodeoxycytidine (gemcitabine). ACS Symp. Ser. 1996, 639 (Biomedical Frontiers of Fluorine Chemistry), 265278,  DOI: 10.1021/bk-1996-0639.ch019
      219. 219
        (a) Bender, D. M.; Bao, J.; Dantzig, A. H.; Diseroad, W. D.; Law, K. L.; Magnus, N. A.; Peterson, J. A.; Perkins, E. J.; Pu, Y.; Reutzel-Edens, S. M.; Remick, D. M.; Starling, J. J.; Stephenson, G. A.; Vaid, R. K.; Zhang, D.; McCarthy, J. R. Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine. J. Med. Chem. 2009, 52, 69586961,  DOI: 10.1021/jm901181h .
        (b) Pratt, S. E.; Durland-Busbice, S.; Shepard, R. L.; Heinz-Taheny, K.; Iversen, P. W.; Dantzig, A. H. Human carboxylesterase-2 hydrolyzes the prodrug of gemcitabine (LY2334737) and confers prodrug sensitivity to cancer cells. Clin. Cancer Res. 2013, 19, 11591168,  DOI: 10.1158/1078-0432.CCR-12-1184
      220. 220
        (a) Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, H. M.; Steuer, M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J. Med. Chem. 2010, 53, 72027218,  DOI: 10.1021/jm100863x .
        (b) Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A. M.; Otto, M. J.; Sofia, M. J.; Furman, P. A. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem. 2010, 285, 3433734347,  DOI: 10.1074/jbc.M110.161802
      221. 221
        (a) Kawaguchi, T.; Fukushima, S.; Ohmura, M.; Mishima, M.; Nakano, M. Enzymatic and chemical stability of 2′,3′-dideoxy-2′,3′-didehydropyrimidine nucleosides: potential anti-acquired immunodeficiency syndrome agents. Chem. Pharm. Bull. 1989, 37, 19441945,  DOI: 10.1248/cpb.37.1944 .
        (b) Shi, J.; Ray, A. S.; Mathew, J. S.; Anderson, K. S.; Chu, C. K.; Schinazi, R. F. 2,3-Didehydro-2,3-dideoxynucleosides are degraded to furfuryl alcohol under acidic conditions. Bioorg. Med. Chem. Lett. 2004, 14, 21592162,  DOI: 10.1016/j.bmcl.2004.02.031
      222. 222
        Ray, A. S.; Hernandez-Santiago, B. I.; Mathew, J. S.; Murakami, E.; Bozeman, C.; Xie, M.-Y.; Dutschman, G. E.; Gullen, E.; Yang, Z.; Hurwitz, S.; Cheng, Y.-C.; Chu, C. K.; McClure, H.; Schinazi, R. F.; Anderson, K. S. Mechanism of anti-human immunodeficiency virus activity of β-d-6-cyclopropylamino-2′,3′-didehydro-2′,3′-dideoxyguanosine. Antimicrob. Agents Chemother. 2005, 49, 19942001,  DOI: 10.1128/AAC.49.5.1994-2001.2005
      223. 223
        (a) Rana, K. Z.; Dudley, M. N. Clinical pharmacokinetics of stavudine. Clin. Pharmacokinet. 1997, 33, 276284,  DOI: 10.2165/00003088-199733040-00003 .
        (b) Becher, F.; Landman, R.; Mboup, S.; Kane, C. N.; Canestri, A.; Liegeois, F.; Vray, M.; Prevot, M. H.; Leleu, G.; Benech, H. Monitoring of didanosine and stavudine intracellular trisphosphorylated anabolite concentrations in HIV-infected patients. AIDS 2004, 18, 181187,  DOI: 10.1097/00002030-200401230-00006
      224. 224
        (a) Schaeffer, H. J.; Beauchamp, L.; Miranda, de P.; Elion, G. B.; Bauer, D. J.; Collins, P. 9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group. Nature 1978, 272, 583585,  DOI: 10.1038/272583a0 .
        (b) Faulds, D.; Heel, R. C. Ganciclovir, A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs 1990, 39, 597638,  DOI: 10.2165/00003495-199039040-00008
      225. 225
        (a) Soul-Lawton, J.; Seaber, E.; On, N.; Wootton, R.; Rolan, P.; Posner, J. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob. Agents Chemother. 1995, 39, 27592764,  DOI: 10.1128/AAC.39.12.2759 .
        (b) Abete, J. F.; Martín-Davila, P.; Moreno, S.; Quijino, Y.; Vicente, E.; Pou, L. Pharmacokinetics of oral valganciclovir and intravenous ganciclovir administered to prevent cytomegalovirus disease in an adult patient receiving small-intestine transplantation. Antimicrob. Agents Chemother. 2004, 48, 27822783,  DOI: 10.1128/AAC.48.7.2782-2783.2004
      226. 226
        (a) de Vrueh, R. L. A.; Smith, P. L.; Lee, C. P. Transport of L-valine-acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2. J. Pharmacol. Exp. Ther. 1998, 286, 11661170.
        (b) Han, H. K.; de Vrueh, R. L. A.; Rhie, J. K.; Covitz, K. M. Y.; Smith, P. L.; Lee, C. P.; Oh, D. M.; Sadee, W.; Amidon, G. L. 5′-Amino acid esters of antiviral nucleosides, acyclovir and AZT, are absorbed by the intestinal PEPT1 peptide transporter. Pharm. Res. 1998, 15, 11541159,  DOI: 10.1023/A:1011919319810 .
        (c) Sugawara, M.; Huang, W.; Fei, Y. J.; Leibach, F. H.; Ganapathy, V.; Ganapathy, M. E. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J. Pharm. Sci. 2000, 89, 781789,  DOI: 10.1002/(SICI)1520-6017(200006)89:6<781::AID-JPS10>3.0.CO;2-7
      227. 227
        (a) Bonvicini, P.; Levi, A.; Lucchini, V.; Modena, G.; Scorrano, G. Acid-base behavior of alkyl sulfur and oxygen bases. J. Am. Chem. Soc. 1973, 95, 59605964,  DOI: 10.1021/ja00799a023 .
        (b) Fife, T. H.; Jao, L. K. The acid-catalyzed hydrolysis of 2-(substituted phenyl)-1,3-oxathiolanes. J. Am. Chem. Soc. 1969, 91, 42174220,  DOI: 10.1021/ja01043a034
      228. 228
        Chandrasekhar, S.; Chopra, D.; Gopalaiah, K.; Row, T. The generalized anomeric effect in the 1,3-thiazolidines: Evidence for both sulphur and nitrogen as electron donors. Crystal structures of various N-acylthiazolidines including mercury(II) complexes. Possible relevance to penicillin action. J. Mol. Struct. 2007, 837, 118131,  DOI: 10.1016/j.molstruc.2006.10.034
      229. 229
        Dionne, G. 3TC: a Canadian scientific success story. McGill Journal of Medicine (MJM). 1999, 5, 6065
      230. 230
        Liotta, D. C.; Painter, G. R. Discovery and development of the anti-human immunodeficiency virus drug, emtricitabine (emtriva, FTC). Acc. Chem. Res. 2016, 49, 20912098,  DOI: 10.1021/acs.accounts.6b00274
      231. 231
        (a) Gumina, G.; Song, G.; Chu, C. K. L-Nucleosides as chemotherapeutic agents. FEMS Microbiol. Lett. 2001, 202, 915,  DOI: 10.1016/S0378-1097(01)00285-3 .
        (b) Kim, H. O.; Shanmuganatban, K.; Alves, A. J.; Jeong, L. S.; Beacb, J. W.; Schinazi, R. F.; Chang, C.; Cheng, Y.; Chu, C. K. Potent anti-HIV and anti-HBV activities of (−)-L-β-dioxolane-C and (+)-L-β-dioxolane-T and their asymmetric syntheses. Tetrahedron Lett. 1992, 33, 68996902,  DOI: 10.1016/S0040-4039(00)60890-0
      232. 232
        (a) Grove, K. L.; Guo, X.; Liu, S.-H.; Gao, Z.; Chu, C. K.; Cheng, Y.-C. Anticancer activity of β-l-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration. Cancer Res. 1995, 55, 30083011.
        (b) Lapointe, R.; Letourneau, R.; Steward, W.; Hawkins, R. E.; Batist, G.; Vincent, M.; Whittom, R.; Eatock, M.; Jolivet, J.; Moore, M. Phase II study of troxacitabine in chemotherapy-naïve patients with advanced cancer of the pancreas. Annals Oncol. 2005, 16, 289293,  DOI: 10.1093/annonc/mdi061 .
        (c) Moore, L. E.; Boudinot, F. D.; Chu, C. K. Preclinical pharmacokinetics of β-L-dioxolane-cytidine, a novel anticancer agent, in rats. Cancer Chemother. Pharmacol. 1997, 39, 532536,  DOI: 10.1007/s002800050609 .
        (d) Swords, R.; Giles, F. Troxacitabine in acute leukemia. Hematology 2007, 12, 219227,  DOI: 10.1080/10245330701406881
      233. 233
        Lin, J.; Kira, T.; Gullen, E.; Choi, Y.; Qu, F.; Chu, C. K.; Cheng, Y. Structure-activity relationships of L-dioxolane uracil nucleosides as anti-Epstein Barr virus agents. J. Med. Chem. 1999, 42, 22122217,  DOI: 10.1021/jm9806749
      234. 234
        Liang, C.; Lee, D. W.; Newton, M. G.; Chu, C. K. Synthesis of L-dioxolane nucleosides and related chemistry. J. Org. Chem. 1995, 60, 15461553,  DOI: 10.1021/jo00111a012
      235. 235
        (a) Goodwin, N. C.; Mabon, R.; Harrison, B. A.; Shadoan, M. K.; Almstead, Z. Y.; Xie, Y.; Healy, J.; Buhring, L. M.; DaCosta, C. M.; Bardenhagen, J.; Mseeh, F.; Liu, Q.; Nouraldeen, A.; Wilson, A. G.; Kimball, D.; Powell, D. R.; Rawlins, D. B. Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes. J. Med. Chem. 2009, 52, 62016204,  DOI: 10.1021/jm900951n .
        (b) Goodwin, N. C.; Ding, Z.; Harrison, B. A.; Strobel, E. D.; Harris, A. L.; Smith, M.; Thompson, A. Y.; Xiong, W.; Mseeh, F.; Bruce, D. J.; Diaz, D.; Gopinathan, S.; Li, L.; O’Neill, E.; Thiel, M.; Wilson, A. G.; Carson, K. G.; Powell, D. R.; Rawlins, D. B. Discovery of LX2761, a sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor restricted to the intestinal lumen, for the treatment of diabetes. J. Med. Chem. 2017, 60, 710721,  DOI: 10.1021/acs.jmedchem.6b01541
      236. 236
        Fioretto, P.; Zambon, A.; Rossato, M.; Busetto, L.; Vettor, R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care 2016, 39, S165S171,  DOI: 10.2337/dcS15-3006
      237. 237
        (a) Selnick, H. G.; Hess, J. F.; Tang, C.; Liu, K.; Schachter, J. B.; Ballard, J. E.; Marcus, J.; Klein, D. J.; Wang, X.; Pearson, M.; Savage, M. J.; Kaul, R.; Li, T.-S.; Vocadlo, D. J.; Zhou, Y.; Zhu, Y.; Mu, C.; Wang, Y.; Wei, Z.; Bai, C.; Duffy, J. L.; McEachern, E. J. Discovery of MK-8719, a potent O-GlcNAcase inhibitor as a potential treatment for tauopathies. J. Med. Chem. 2019, 62, 1006210097,  DOI: 10.1021/acs.jmedchem.9b01090 .
        (b) Wang, X.; Li, W.; Marcus, J.; Pearson, M.; Song, L.; Smith, K.; Terracina, G.; Lee, J.; Hong, K. K.; Lu, S. X.; Hyde, L.; Chen, S. C.; Kinsley, D.; Melchor, J. P.; Rubins, D. J.; Meng, X.; Hostetler, E.; Sur, C.; Zhang, L.; Schachter, J. B.; Hess, J. F.; Senick, H. G.; Vocadlo, D. J.; McEachern, E. J.; Uslaner, J. M.; Duffy, J. L.; Smith, S. M. MK-8719, a novel and selective O-GlcNAcase inhibitor that reduces the formation of pathological tau and ameliorates neurodegeneration in a mouse model of tauopathy. J. Pharmacol. Exp. Ther. 2020, 374, 252263,  DOI: 10.1124/jpet.120.266122
      238. 238
        Passioura, T.; Watashi, K.; Fukano, K.; Shimura, S.; Saso, W.; Morishita, R.; Ogasawara, Y.; Tanaka, Y.; Mizokami, M.; Sureau, C.; Suga, H.; Wakita, T. De novo macrocyclic peptide inhibitors of hepatitis B virus cellular entry. Cell Chem. Biol. 2018, 25, 906915,  DOI: 10.1016/j.chembiol.2018.04.011
      239. 239
        Liu, Y.; Ruan, H.; Li, Y.; Sun, G.; Liu, X.; He, W.; Mao, F.; He, M.; Yan, L.; Zhong, G.; Yan, H.; Li, W.; Zhang, Z. Potent and specific inhibition of NTCP-mediated HBV/HDV infection and substrate transporting by a novel, oral-available cyclosporine a analogue. J. Med. Chem. 2021, 64, 543565,  DOI: 10.1021/acs.jmedchem.0c01484
      240. 240
        (a) Satchell, D. P. N.; Satchell, R. S. Mechanisms of hydrolysis of thioacetals. Chem. Soc. Rev. 1990, 19, 5581,  DOI: 10.1039/cs9901900055 .
        (b) Ali, M.; Satchell, D. P. N. Kinetics and mechanism of hydrolysis of open-chain thioacetals derived from benzophenone and the reactivity of α-thiophenyl carbocations. J. Chem. Soc., Perkin Trans. 2 1995, 167170,  DOI: 10.1039/P29950000167
      241. 241
        Burghardt, T. E. Developments in the deprotection of thioacetals. J. Sulfur Chem. 2005, 26, 411427,  DOI: 10.1080/17415990500195198
      242. 242
        Cushman, D. W.; Ondetti, M. A. Personal and historical perspectives. History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension 1991, 17, 589592,  DOI: 10.1161/01.HYP.17.4.589
      243. 243
        Patchett, A. A. Excursions in drug discovery. J. Med. Chem. 1993, 36, 20512058,  DOI: 10.1021/jm00067a001
      244. 244
        Smith, E. M.; Swiss, G. F.; Neustadt, B. R.; McNamara, P.; Gold, E. H.; Sybertz, E. J.; Baum, T. Angiotensin converting enzyme inhibitors: spirapril and related compounds. J. Med. Chem. 1989, 32, 16001606,  DOI: 10.1021/jm00127a033
      245. 245
        Noble, S.; Sorkin, E. M. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension. Drugs 1995, 49, 750766,  DOI: 10.2165/00003495-199549050-00008
      246. 246
        Sybertz, E. J.; Watkins, R. W.; Ahn, H. S.; Baum, T.; La Rocca, P.; Patrick, J.; Leitz, F. Pharmacologic, metabolic, and toxicologic profile of spirapril (SCH 33844), a new angiotensin converting inhibitor. J. Cardiovasc. Pharmacol. 1987, 10, S105S108,  DOI: 10.1097/00005344-198706107-00020
      247. 247
        Guitard, C.; Lohmann, F. W.; Alfiero, R.; Ruina, M.; Alvisi, V. Cardiovasc. Drugs Ther. 1997, 11, 449457,  DOI: 10.1023/A:1007797405850
      248. 248
        (a) Yamashita, S.; Matsuzawa, Y. Where are we with probucol: a new life for an old drug?. Atherosclerosis 2009, 207, 1623,  DOI: 10.1016/j.atherosclerosis.2009.04.002 .
        (b) Buckley, M. M.-T.; Goa, K. L.; Price, A. H.; Brogden, R. N. A reappraisal of its pharmacological properties and therapeutic use in hypercholesterolaemia. Drugs 1989, 37, 761800,  DOI: 10.2165/00003495-198937060-00002
      249. 249
        (a) Neuworth, M. B.; Laufer, R. J.; Barnhart, J. W.; Sefranka, J. A.; McIntosh, D. D. Synthesis and hypocholesterolemic activity of alkylidenedithio bisphenols. J. Med. Chem. 1970, 13, 722725,  DOI: 10.1021/jm00298a031 .
        (b) Carew, T. E.; Schwenke, D. C.; Steinberg, D. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: Evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc. Natl. Acad. Sci. U. S. A. 1987, 84, 77257729,  DOI: 10.1073/pnas.84.21.7725
      250. 250
        Meng, C. Q.; Somers, P. K.; Hoong, L. K.; Zheng, X. S.; Ye, Z.; Worsencroft, K. J.; Simpson, J. E.; Hotema, M. R.; Weingarten, M. D.; MacDonald, M. L.; Hill, R. R.; Marino, E. M.; Suen, K.-L.; Luchoomun, J.; Kunsch, C.; Landers, L. K.; Stefanopoulos, D.; Howard, R. B.; Sundell, C. L.; Saxena, U.; Wasserman, M. A.; Sikorski, J. A. Discovery of novel phenolic antioxidants as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases. J. Med. Chem. 2004, 47, 64206432,  DOI: 10.1021/jm049685u
      251. 251
        (a) Meng, C. Q.; Somers, P. K.; Rachita, C. L.; Holt, L. A.; Hoong, L. K.; Zheng, X. S.; Simpson, J. E.; Hill, R. R.; Olliff, L. K.; Kunsch, C. K.; Sundell, C. L.; Parthasarathy, S.; Saxena, U.; Sikorski, J. A.; Wasserman, M. A. Novel phenolic antioxidants as multifunctional inhibitors of inducible VCAM-1 expression for use in atherosclerosis. Bioorg. Med. Chem. Lett. 2002, 12, 25452548,  DOI: 10.1016/S0960-894X(02)00516-4 .
        (b) Muldrew, K. M.; Franks, A. M. Succinobucol: review of the metabolic, antiplatelet and cardiovascular effects. Expert Opin. Invest. Drugs 2009, 18, 531539,  DOI: 10.1517/13543780902849244
      252. 252
        (a) Groso, G.; Caputo, O.; Ceruti, M.; Biglino, G.; Franzone, J. S.; Cirillo, R. Synthesis and antibronchospastic activity of theophylline thioacetal derivatives. Eur. J. Med. Chem. 1989, 24, 635638,  DOI: 10.1016/0223-5234(89)90035-4 .
        (b) Franzone, J. S.; Reboani, M. C.; Biglione, V.; Cirillo, R. Pharmacological and toxicological activities of a new methylxanthine derivative [7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine] with antibronchospastic and mucoregulatory properties. Drugs Exp. Clin. Res. 1990, 16, 263276.
        (c) Reboani, M. C.; Franzone, J. S. In vivo anti-inflammatory activity of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine. Drugs Exp. Clin. Res. 1990, 16, 277284.
        (d) Cravanzola, C.; Grosa, G.; Franzone, J. S. Kinetic and metabolic studies of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine in the rat. Drugs Exp. Clin. Res. 1990, 16, 285291.
        (e) Grosa, G.; Caputo, O.; Ceruti, M.; Biglino, G.; Franzone, J. S.; Cravanzola, C. Metabolism of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine by rat liver microsomes. Diastereoselective metabolism of the 1,3-dithiolane ring. Drug Metab. Dispos. 1991, 19, 454457.
        (f) Auret, B. J.; Boyd, D. R.; Dunlop, R.; Drake, A. F. Stereoselectivity during fungal sulphoxidations of 1,3-dithiolanes. J. Chem. Soc., Perkin Trans. 1 1988, 28272829,  DOI: 10.1039/p19880002827
      253. 253
        Fulop, F.; Mattinen, J.; Pihlaja, R. Ring-chain tautomerism in 1,2-thiazolidines. Tetrahedron 1990, 46, 65456552,  DOI: 10.1016/S0040-4020(01)96019-3
      254. 254
        Singh, G. S. β-lactams in the new millennium. Part-II: Cephems, oxacephems, penams and sulbactam. Mini-Rev. Med. Chem. 2004, 4, 93109,  DOI: 10.2174/1389557043487547
      255. 255
        Bush, K.; Bradford, P. A. β-Lactams and β-lactamase inhibitors: an overview. Cold Spring Harbor Perspect. Med. 2016, 6, a025247  DOI: 10.1101/cshperspect.a025247
      256. 256
        Szultka, M.; Krzeminski, R.; Jackowski, M.; Buszewski, B. Identification of in vitro metabolites of amoxicillin in human liver microsomes by LC-ESI/MS. Chromatographia 2014, 77, 10271035,  DOI: 10.1007/s10337-014-2648-2
      257. 257
        Smith, P. W.; Zuccotto, F.; Bates, R. H.; Martinez-Martinez, M. S.; Read, K. D.; Peet, C.; Epemolu, O. Pharmacokinetics of β-lactam antibiotics: clues from the past to help discover long-acting oral drugs in the future. ACS Infect. Dis. 2018, 4, 14391447,  DOI: 10.1021/acsinfecdis.8b00160
      258. 258
        (a) Drawz, S. M.; Bonomo, R. A. Three decades of β-lactamase inhibitors. Clin. Microbiol. Rev. 2010, 23, 160201,  DOI: 10.1128/CMR.00037-09 .
        (b) Gonzalez-Bello, C.; Rodríguez, D.; Pernas, M.; Rodríguez, A.; Colchon, E. β-Lactamase inhibitors to restore the efficacy of antibiotics against superbugs. J. Med. Chem. 2020, 63, 18591881,  DOI: 10.1021/acs.jmedchem.9b01279
      259. 259
        English, A. R.; Retsema, J. A.; Girard, A. E.; Lynch, J. E.; Barth, W. E. CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterization. Antimicrob. Agents Chemother. 1978, 14, 414419,  DOI: 10.1128/AAC.14.3.414
      260. 260
        English, A. R.; Retsema, J. A.; Girard, A. E.; Lynch, J. E.; Barth, W. E. CP-45,899, a β-lactamase inhibitor that extends the antibacterial spectrum of β-lactams: initial bacteriological characterization. Antimicrob. Agents Chemother. 1978, 14, 414419,  DOI: 10.1128/AAC.14.3.414
      261. 261
        Papp-Wallace, K. M.; Bethel, C. R.; Caillon, J.; Barnes, M. D.; Potel, G.; Bajaksouzian, S.; Rutter, J. D.; Reghal, A.; Shapiro, S.; Taracila, M. A.; Jacobs, M. R.; Bonomo, R. A.; Jacqueline, C. Beyond piperacillin-tazobactam: cefepime and AAI101 as a potent β-lactam-β-lactamase inhibitor combination. Antimicrob. Agents Chemother. 2019, 63, e00105  DOI: 10.1128/AAC.00105-19
      262. 262
        Chen, Y. L.; Chang, C. W.; Hedberg, K. Synthesis of a potent β-lactamase inhibitor-1,1-dioxo-6-(2-pyridyl)methylenepenicillanic acid and its reaction with sodium methoxide. Tetrahedron Lett. 1986, 27, 34493452,  DOI: 10.1016/S0040-4039(00)84819-4
      263. 263
        (a) Vazquez-Ucha, J. C.; Maneiro, M.; Martinez-Guitian, M.; Buynak, J.; Bethel, C. R.; Bonomo, R. A.; Bou, G.; Poza, M.; Gonzalez-Bello, C.; Beceiro, A. Activity of the β-lactamase inhibitor LN-1–255 against carbapenem-hydrolyzing class D β-lactamases from Acinetobacter baumannii. Antimicrob. Agents Chemother. 2017, 61, e01172–17  DOI: 10.1128/AAC.01172-17 .
        (b) Vázquez-Ucha, J. C.; Martínez-Guitián, M.; Maneiro, M.; Conde-Perez, K.; Álvarez-Fraga, L.; Torrens, G.; Oliver, A.; Buynak, J. D.; Bonomo, R. A.; Bou, G.; González-Bello, C.; Poza, M.; Beceiro, A. Therapeutic efficacy of LN-1–255 in combination with imipenem in severe infection caused by carbapenem-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 2019, 63, e01092  DOI: 10.1128/AAC.01092-19
      264. 264
        Lee, M.-H. H.; Graham, G. G.; Williams, K. M.; Day, R. O. A benefit-risk assessment of benzbromarone in the treatment of gout: was its withdrawal from the market in the best interest of patients?. Drug Saf. 2008, 31, 643665,  DOI: 10.2165/00002018-200831080-00002
      265. 265
        (a) Uda, J.; Kobashi, S.; Miyata, S.; Ashizawa, N.; Matsumoto, K.; Iwanaga, T. Discovery of dotinurad (FYU-981), a new phenol derivative with highly potent uric acid lowering activity. ACS Med. Chem. Lett. 2020, 11, 20172023,  DOI: 10.1021/acsmedchemlett.0c00176 .
        (b) Omura, K.; Miyata, K.; Kobashi, S.; Ito, A.; Fushimi, M.; Uda, J.; Sasaki, T.; Iwanaga, T.; Ohashi, T. Ideal pharmacokinetic profile of dotinurad as a selective reabsorption inhibitor. Drug Metab. Pharmacokinet. 2020, 35, 313320,  DOI: 10.1016/j.dmpk.2020.03.002
      266. 266
        Hansen, A. H.; Sergeev, E.; Bolognini, D.; Sprenger, R. R.; Ekberg, J. H.; Ejsing, C. S.; McKenzie, C. J.; Ulven, E. R.; Milligan, G.; Ulven, T. Discovery of a potent thiazolidine free fatty acid receptor 2 agonist with favorable pharmacokinetic properties. J. Med. Chem. 2018, 61, 95349550,  DOI: 10.1021/acs.jmedchem.8b00855
      267. 267
        (a) Edmondson, S. D.; Mastracchio, A.; Beconi, M.; Colwell, L. F.; Habulihaz, B.; He, H.; Kumar, S.; Leiting, B.; Lyons, K. A.; Mao, A.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Zhu, L.; Thornberry, N.; Weber, A.; Parmee, E. R. Potent and selective proline derived dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 51515155,  DOI: 10.1016/j.bmcl.2004.07.056 .
        (b) Park, W. S.; Kang, S. K.; Jun, M. A.; Shin, M. S.; Kim, K. Y.; Rhee, S. D.; Bae, M. A.; Kim, M. S.; Kim, K. R.; Kang, N. S.; Yoo, S.; Lee, J. O.; Song, D. Y.; Silinski, P.; Schneider, S. E.; Ahn, J. H.; Kim, S. S. Discovery of β-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 13661370,  DOI: 10.1016/j.bmcl.2011.01.041
      268. 268
        Carzaniga, L.; Amari, G.; Rizzi, A.; Capaldi, C.; Fanti, R. D.; Ghidini, E.; Villetti, G.; Carnini, C.; Moretto, N.; Facchinetti, F.; Caruso, P.; Marchini, G.; Battipaglia, L.; Patacchini, R.; Cenacchi, V.; Volta, R.; Amadei, F.; Pappani, A.; Capacchi, S.; Bagnacani, V.; Delcanale, M.; Puccini, P.; Catinella, S.; Civelli, M.; Armani, E. Discovery and optimization of thiazolidinyl and pyrrolidinyl derivatives as Inhaled PDE4 inhibitors for respiratory diseases. J. Med. Chem. 2017, 60, 1002610046,  DOI: 10.1021/acs.jmedchem.7b01044
      269. 269
        Chen, T.; Reich, N. W.; Bell, N.; Finn, P. D.; Rodriguez, D.; Kohler, J.; Kozuka, K.; He, L.; Spencer, A. G.; Charmot, D.; Navre, M.; Carreras, C. W.; Koo-McCoy, S.; Tabora, J.; Caldwell, J. S.; Jacobs, J. W.; Lewis, J. G. Design of gut-restricted thiazolidine agonists of G protein-coupled bile acid receptor 1 (GPBAR1, TGR5). J. Med. Chem. 2018, 61, 75897613,  DOI: 10.1021/acs.jmedchem.8b00308
      270. 270
        Tobias, P. S.; Kallen, R. G. Kinetics and equilibriums of the reaction of pyridoxal 5′-phosphate with ethylenediamine to form Schiff bases and cyclic geminal diamines. Evidence for kinetically competent geminal diamine intermediates in transimination sequences. J. Am. Chem. Soc. 1975, 97, 65306539,  DOI: 10.1021/ja00855a041
      271. 271
        Faine, S.; Harper, M. Independent antibiotic actions of hetacillin and ampicillin revealed by fast methods. Antimicrob. Agents Chemother. 1973, 3, 1518,  DOI: 10.1128/AAC.3.1.15
      272. 272
        (a) Balkovec, J. M.; Hughes, D. L.; Masurekar, P. S.; Sable, C. A.; Schwartz, R. E.; Singh, S. B. Discovery and development of first in class antifungal caspofungin (CANCIDAS®) - a case study. Nat. Prod. Rep. 2014, 31, 1534,  DOI: 10.1039/C3NP70070D .
        (b) Bouffard, F. A.; Hammond, M. L.; Arison, B. H. Pneumocandin Bo acid degradate. Tetrahedron Lett. 1995, 36, 14051408,  DOI: 10.1016/0040-4039(95)00017-7
      273. 273
        Kurtz, M. B.; Douglas, C.; Marrinan, J.; Nollstadt, K.; Onishi, J.; Dreikorn, S.; Milligan, J.; Mandala, S.; Thompson, J.; Balkovec, J. M. Increased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis. Antimicrob. Agents Chemother. 1994, 38, 27502757,  DOI: 10.1128/AAC.38.12.2750
      274. 274
        (a) Bartizal, K.; Gill, C. J.; Abruzzo, G. K.; Flattery, A. M.; Kong, L.; Scott, P. M.; Smith, J. G.; Leighton, C. E.; Bouffard, A.; Dropinski, J. F.; Balkovec, J. In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872). Antimicrob. Agents Chemother. 1997, 41, 23262332,  DOI: 10.1128/AAC.41.11.2326 .
        (b) Hajdu, R.; Thompson, R.; Sundelof, J. G.; Pelak, B. A.; Bouffard, F. A.; Dropinski, J. F.; Kropp, H. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872). Antimicrob. Agents Chemother. 1997, 41, 23392344,  DOI: 10.1128/AAC.41.11.2339
      275. 275
        (a) Snyder, L. B.; Meng, Z.; Mate, R.; D’Andrea, S. V.; Marinier, A.; Quesnelle, C. A.; Gill, P.; DenBleyker, K. L.; Fung-Tomc, J. C.; Frosco, M.; Martel, A.; Barrett, J. F.; Bronson, J. J. Discovery of isoxazolinone antibacterial agents. Nitrogen as a replacement for the stereogenic center found in oxazolidinone antibacterials. Bioorg. Med. Chem. Lett. 2004, 14, 47354739,  DOI: 10.1016/j.bmcl.2004.06.076 .
        (b) Quesnelle, C. A.; Gill, P.; Roy, S.; Dodier, M.; Marinier, A.; Martel, A.; Snyder, L. B.; D’Andrea, S. V.; Bronson, J. J.; Frosco, M.; Beaulieu, D.; Warr, G. A.; DenBleyker, K. L.; Stickle, T. M.; Yang, H.; Chaniewski, S. E.; Ferraro, C. A.; Taylor, D.; Russell, J. W.; Santone, K. S.; Clarke, J.; Drain, R. L.; Knipe, J. O.; Mosure, K.; Barrett, J. F. Biaryl isoxazolinone antibacterial agents. Bioorg. Med. Chem. Lett. 2005, 15, 27282733,  DOI: 10.1016/j.bmcl.2005.04.003
      276. 276
        Kees, K. L.; Caggiano, T. J.; Steiner, K. E.; Fitzgerald, J. J., Jr.; Kates, M. J.; Christos, T. E.; Kulishoff, J. M., Jr.; Moore, R. D.; McCaleb, M. L. Studies on new acidic azoles as glucose-lowering agents in obese, diabetic db/db mice. J. Med. Chem. 1995, 38, 617628,  DOI: 10.1021/jm00004a008
      277. 277
        (a) Noshi, T.; Kitano, M.; Taniguchi, K.; Yamamoto, A.; Omoto, S.; Baba, K.; Hashimoto, T.; Ishida, K.; Kushima, Y.; Hattori, K.; Kawai, M.; Yoshida, R.; Kobayashi, M.; Yoshinaga, T.; Sato, A.; Okamatsu, M.; Sakoda, Y.; Kida, H.; Shishido, T.; Naito, A. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res. 2018, 160, 109117,  DOI: 10.1016/j.antiviral.2018.10.008 .
        (b) Miyagawa, M.; Akiyama, T.; Taoda, Y.; Takaya, K.; Takahashi-Kageyama, C.; Tomita, K.; Yasuo, K.; Hattori, K.; Shano, S.; Yoshida, R.; Shishido, T.; Yoshinaga, T.; Sato, A.; Kawai, M. Synthesis and SAR study of carbamoyl pyridone bicyclederivatives as potent inhibitors of influenza cap-dependent endonuclease. J. Med. Chem. 2019, 62, 81018114,  DOI: 10.1021/acs.jmedchem.9b00861
      278. 278
        Taoda, Y.; Miyagawa, M.; Akiyama, T.; Tomita, K.; Hasegawa, Y.; Yoshida, R.; Noshi, T.; Shishido, T.; Kawai, M. Dihydrodibenzothiepine: promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitor. Bioorg. Med. Chem. Lett. 2020, 30, 127547,  DOI: 10.1016/j.bmcl.2020.127547
      279. 279
        (a) Heo, Y.-A. Baloxavir: first global approval. Drugs 2018, 78, 693697,  DOI: 10.1007/s40265-018-0899-1 .
        (b) Shirley, M. Baloxavir marboxil: a review in acute uncomplicated influenza. Drugs 2020, 80, 11091118,  DOI: 10.1007/s40265-020-01350-8
      280. 280
        Raheem, I. T.; Walji, A. M.; Klein, D.; Sanders, J. M.; Powell, D. A.; Abeywickrema, P.; Barbe, G.; Bennet, A.; Clas, S.; Dubost, D.; Embrey, M.; Grobler, J.; Hafey, M. J.; Hartingh, T. J.; Hazuda, D. J.; Miller, M. D.; Moore, K. P.; Pajkovic, N.; Patel, S.; Rada, V.; Rearden, P.; Schreier, J. D.; Sisko, J.; Steele, T. G.; Truchon, J.; Wai, J.; Xu, M.; Coleman, P. J. Discovery of 2-pyridinone aminals: a prodrug strategy to advance a second generation of HIV-1 integrase strand transfer inhibitors. J. Med. Chem. 2015, 58, 81548165,  DOI: 10.1021/acs.jmedchem.5b01037
      281. 281
        Reich, S. H.; Sprengeler, P. A.; Chiang, G. G.; Appleman, J. R.; Chen, J.; Clarine, J.; Eam, B.; Ernst, J. T.; Han, Q.; Goel, V. K.; Han, E.; Huang, V.; Hung, I.; Jemison, A.; Jessen, K. A.; Molter, J.; Murphy, D.; Neal, M.; Parker, G. S.; Shaghafi, M.; Sperry, S.; Staunton, J.; Stumpf, C. R.; Thompson, P. A.; Tran, C.; Webber, S. E.; Wegerski, C. J.; Zheng, H.; Webster, K. R. Structure-based design of pyridone-aminal eFT508 targeting dysregulated translation by selective mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) inhibition. J. Med. Chem. 2018, 61, 35163540,  DOI: 10.1021/acs.jmedchem.7b01795
      282. 282
        Paulini, R.; Laus Müller, K.; Diederich, F. Orthogonal multipolar interactions in structural chemistry and biology. Angew. Chem., Int. Ed. 2005, 44, 17881805,  DOI: 10.1002/anie.200462213
      283. 283
        A study to evaluate the efficacy and safety of TAK-906 in adult participants with symptomatic idiopathic or diabetic gastroparesis. https://clinicaltrials.gov/ct2/show/NCT03544229 (accessed April 29, 2021).
      284. 284
        Whiting, R. L.; Darpo, B.; Chen, C.; Fletcher, M.; Combs, D.; Xue, H.; Stoltz, R. R. Safety, pharmacokinetics, and pharmacodynamics of trazpiroben (TAK-906), a novel selective D2/D3 receptor antagonist: a Phase 1 randomized, placebo-controlled single- and multiple-dose escalation study in healthy participants. Clin. Pharmacol. Drug Dev. 2021, in press.  DOI: 10.1002/cpdd.906 . Epub ahead of print. PMID: 33462988.
      285. 285
        A study to evaluate the safety and efficacy of NG101 in adult participants with symptomatic diabetic or idiopathic gastroparesis. https://clinicaltrials.gov/ct2/show/NCT04303195 (accessed April 29, 2021).
      286. 286
        Nishihara, M.; Ramsden, D.; Balani, S. K. Evaluation of the drug-drug interaction potential for trazpiroben (TAK-906), a D2/D3 receptor antagonist for gastroparesis, towards cytochrome P450s and transporters. Xenobiotica 2021 in press. 51 668 DOI: 10.1080/00498254.2021.1912438 .
      287. 287
        (a) Bond, S.; Draffan, A. G.; Fenner, J. E.; Lambert, J.; Lim, C. Y.; Lin, B.; Luttick, A.; Mitchell, J. P.; Morton, C. J.; Nearn, R. H.; Sanford, V.; Stanislawski, P. C.; Tucker, S. P. The discovery of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 1. Bioorg. Med. Chem. Lett. 2015, 25, 969975,  DOI: 10.1016/j.bmcl.2014.11.018 .
        (b) Bond, S.; Draffan, A. G.; Fenner, J. E.; Lambert, J.; Lim, C. Y.; Lin, B.; Luttick, A.; Mitchell, J. P.; Morton, C. J.; Nearn, R. H.; Sanford, V.; Anderson, K. H.; Mayes, P. A.; Tucker, S. P. 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 2: Identification of BTA9881 as a preclinical candidate. Bioorg. Med. Chem. Lett. 2015, 25, 976981,  DOI: 10.1016/j.bmcl.2014.11.024
      288. 288
        Gentry, P. R.; Kokubo, M.; Bridges, T. M.; Kett, N. R.; Harp, J. M.; Cho, H. P.; Smith, E.; Chase, P.; Hodder, P. S.; Niswender, C. M.; Daniels, J. S.; Conn, P. J.; Wood, M. R.; Lindsley, C. M. Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). J. Med. Chem. 2013, 56, 93519355,  DOI: 10.1021/jm4013246

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect

    This website uses cookies to improve your user experience. By continuing to use the site, you are accepting our use of cookies. Read the ACS privacy policy.

    CONTINUE